Journal of Clinical Oncology (JCO) Podcast

Shannon Westin, Pamela Kunz, and Rachna Shroff discuss the lack of gender equity on oncology industry advisory boards. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast; our podcast where we get in-depth for articles in the Journal of Clinical Oncology. I am your fearless leader, and host, Shannon Westin, the Social Media Editor for the JCO, as well as a Professor of Gynecologic Oncology at MD Anderson Cancer Center. And I am so excited to introduce our two guests today. We are going to be discussing the article from the JCO, 'Where Are All the Women in Industry Advisory Boards?' And none of my guests have Conflict of Interest related to this work. So, first, let me introduce Dr. Rachna Shroff, she is from the University of Arizona, Tucson. She's not only the Interim Chief of the Division of Hematology/Oncology, she's the Associate Dean of Clinical and Translational Research, and Associate Professor of Medicine, the Chief of the Section of GI Medical Oncology, and the leader of the GI Clinical Research team. And somehow, we got her on this podcast. I don't know how she had the time. Welcome. Dr. Rachna Shroff: Thank you. So excited to be here. Dr. Shannon Westin: She is the first author on this paper, and she's also accompanied by the last author on this paper, Dr. Pamela Kunz, from the Yale School of Medicine, where she serves as Associate Professor of Internal Medicine, the Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital, and Yale Cancer Center, the Chief of GI Medical Oncology, and the Vice Chief of Diversity, Equity, and Inclusion in Medical Oncology. Welcome. Dr. Pamela Kunz: Thank you. Really excited for this. Dr. Shannon Westin: I have to step up my game, man. This is an esteemed panel here. So, we're going to get right to it. I think this is such an important topic because you know, we've been seeing quite a bit of focus on gender equity in Oncology, I would say, really over the last five years, really, especially - yay. Where do you all see the biggest gaps? Like, what are we missing? What do we need to do? Dr. Rachna Shroff: Well, I'm happy to chime in, and I know that Dr. Kunz has her thoughts as well, but I agree with you. I think the first step to trying to address these gaps is just opening the conversation, and I think we have made tremendous strides in that regard. In terms of gaps, I mean, half of the reason that we even started thinking about this topic was really related to research, and opportunities for clinical trials, clinical research, drug development, and where women can try to increase their visibility and their opportunities. And the honest truth is, some of these things we see day-to-day when we see the number of women at the podium presenting pivotal trials, and the number of women that are lead authors on practice-changing papers. And that, I think, is really an area that needs to be talked about. And then, we need to work on the opportunities for solving these problems and coming up with solutions with everybody around the table, all of the key stakeholders engaged. Dr. Pamela Kunz: I completely agree. And you know, I think that because Dr. Shroff and I are both in the clinical trials space, you know, she and I have talked about this, and I think that industry-sponsored clinical trials are certainly one space, national clinical trial network trials are another space that we are also trying to move the needle, and I think that we really all have a collective responsibility in whatever we're doing to really try to ensure equity and representation, both of women, but also underrepresented minorities. And I think that the way I really like to personally think about this is, as Dr. Shroff said, if we can diversify the people who are leading the science, whether it's clinical trials, basic or translational, our science will in fact be better. We will ask more innovative, creative questions, and our patients will benefit from it. We will have more, I think, health equity because different people will be thinking about how to do the science. So, it's really critical and I think it's something that it is really exciting. I agree with you, Dr. Weston, that it's, "Yay," that we're having some recognition of this. And I think really step one is collecting data, benchmarking, figuring how we can do better. Dr. Shannon Westin: Yes. And I think that's a really nice segue to get into kind of what led you to explore this current area of focus around advisory board participation, and why that matters Dr. Pamela Kunz: Dr. Shroff, should I tell the story? Dr. Rachna Shroff: I was going to say, "Should we share our story?" Dr. Shannon Westin: Oh, I love a story. Yeah, definitely. Dr. Pamela Kunz: Oh, it's a good story. It's a good story. It involves Dr. Brian Alexander, who is one of our co-authors in this and is at Foundation. So, I was invite

Dr. Shannon Westin discusses germline genetic testing in gastrointestinal cancer with Heather Hampel and Dr. Matthew B. Yurgelun. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. This is our podcast where we get down in the nitty-gritty of articles that are published in the Journal of Clinical Oncology. I am your fearless leader and host, Shannon Westin, the Social Media Editor of the Journal of Clinical Oncology, as well as Professor of Gynecologic Oncology at The University of Texas, MD Anderson Cancer Center. And I am very excited to bring two guests in today to discuss a review article that was published in a special series on, 'Precision Medicine and Immunotherapy in GI Malignancies,' back in June of 2022, and this is, 'Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?' And please note that our participants have noted no Conflict of Interest. So, without further ado, let me welcome our guests. First is Heather Hampel. She is a Cancer Genetic Counselor, and the Associate Director in the Division of Clinical Cancer Genomics, and a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Welcome, Heather. Heather Hampel: Thanks so much for having me. Shannon Westin: We're also accompanied by Dr. Matthew Yurgelun, he is a Senior Physician in Medical Oncology at the Dana-Farber Cancer Institute, the Director of the Lynch Syndrome Center, and Assistant Professor of Medicine at Harvard Medical School. Welcome. Dr. Matthew Yurgelun: Thanks for having me. Shannon Westin: And we have all decided we were going by first names. So, audience, don't be alarmed. Okay, let's get right into it. So, this is a really great review. I learned a ton and I think, you know, just to kind of get back to basics, I think we've been seeing an increase in the use of germline genetic testing across a number of different cancer types. As I mentioned, I'm a gynecologic oncologist, certainly this is something we're doing for patients with ovarian cancer. What are the reasons this has become so widespread across all cancer types? Heather Hampel: Matt and I probably agree on this one. I will, but I'll say you a couple of reasons, and see if Matt has any to add. I think that 2013 marked a major turning point in the field of cancer genetics for a couple of reasons. One was; the advent of next-generation sequencing, so that we could do multiple genes at the same time for a lower cost. The other was that that was the year the Supreme Court struck down the patent on BRCA1 and BRCA2, which allowed lots of different competitors into the market to offer sort of these pan-cancer panels, including, BRCA1 and BRCA2, among other genes. And the price has dropped precipitously since then, giving better access for patients. The competition, I think, has been good, so that a lot of the laboratories now will offer out-of-pocket maximums of $250. And then, we've seen a lot of research. Because of that, I think, where we've just done pan-cancer panels on different solid tumor cancers, just to determine what the prevalence of mutations is, all of this is sort of leading to, I think, just greater use of germline genetic testing across the board. I don't know. Matt, what do you think? Dr. Matthew Yurgelun: No, I fully agree. This is an example of the more you look, the more you find, and I think we've seen that both in the studies that have been done looking at multi-gene panel testing in virtually any setting across different cancer types and then I think people who use these in clinical practice, whether they are genetic counselors, oncologists, gastroenterologists, gynecologists, primary care physicians, I think as people have become more experienced and more comfortable using them in routine practice—I think it's not an uncommon phenomenon for those of us who use these to find things that were somewhat unexpected, which kind of naturally leads to the question, "Well, what else might I be missing if I'm not doing these tests further and wider?" What's made it a little bit difficult is that this is an example of testing that's become available commercially before we really understood how to use it. And so, we've been figuring a lot of this out kind of on the fly a little bit. Shannon Westin: Yeah. I think it brings up, and not to get too nitty-gritty right from the beginning, but to me, it brings up the whole idea around variance of uncertain significance, right? I think we've really struggled with this on the GYN space, and I don't know how common that is for you all in the colorectal space, but we get answers, we don't know how to tell a patient what to do with that information. And in fact, we've personally seen people get risk-reducing surgeries, probably not appropriately in response to these variants. Dr. Matthew Yurgelun: It's a real phenomen

On this episode, our guests discuss how postmortem tissue donation can provide meaning to patients and their loved ones. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. This is when we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. Excited to be here today to discuss a really awesome paper. It was a Comments and Controversies named "Postmortem Tissue Donation: Giving Families the Ability to Choose," just published on August 26th, 2022. And I'm joined by a number of the authors. It's going to be a really incredible discussion. I'd like to introduce each of them, and then we'll get right down to it. First is Allen Gustafson. He is the founder of the Swifty Foundation, which he started with his son, Michael, who sadly died in 2013 of medulloblastoma. And this foundation really was the catalyst of the group Gift from a Child, which we're going to really discuss today. In addition, I'm accompanied by Dr. Angela Waanders, the Interim Head of Neuro-Oncology and the Director of Precision Medicine and Associate Professor at the Ann & Robert H. Lurie Children's Hospital of Chicago; Beth Frenkel, a Tissue Navigator at the Children's Hospital of Philadelphia; and Dr. Mateusz Koptyra, a Senior Scientist and the Director of the Center for Data-Driven Discovery in Biomedicine at the Children's Hospital of Philadelphia. So, thank you all for being here. I'm so excited to discuss this paper. I think this is something that our listeners are going to be really interested in and really want to move forward. So, welcome. Allen Gustafson: Thank you. Dr. Mateusz Koptyra: Good morning. Dr. Shannon Westin: So, let's get started. You know, postmortem tissue donation is so critical for research and improving outcomes for our survivors. I think the best way to start, I'd be very interested to hear how each of you got involved with this. And Allen, let's start with you because I think that your story is so important. Allen Gustafson: Sure. Thanks, Shannon. Well, as you mentioned, our son, Michael, died of medulloblastoma in 2013 at the age of 15, and probably about four months before he died, he knew his life was going to end. And he got the idea of donating his body to science, so they could use him to find the cure. And he used to refer to that as his master plan. So, obviously, that charge was put on his mom and I to figure out how he could do that. And although we were being treated by two excellent hospitals, one here in Chicago and one in Boston, they were not helpful in terms of helping us with his final wish. And so, it was really through Nancy Goodman from Kids vs Cancer and his pediatrician going above and beyond the call of duty that Michael was finally able to donate his spine and his brain, some of which was sent to Texas Children's and some of it was sent to SickKids. And it became both very meaningful for him as his life ended, and it was also very meaningful for us in terms of the important step we took as a family in our grieving and our loss of him. And as you mentioned, our work with the Swifty Foundation, really, his choice there was prescient, in that we didn't realize how important postmortem collection is for advancing scientific discovery, nor did we realize how important this could be for other families. So, it all started with his experience in terms of our journey with Gift from a Child. Dr. Shannon Westin: That's so incredible. I'm so glad that you chose to do this work. Dr. Waanders, do you want to pipe in? Dr. Angela Waanders: Yes. So, I think reflecting back, it really was a serendipitous moment in meeting with Patti and Al. I can still remember it was in 2016, I believe, at a Children's Brain Tumor Network annual meeting. I'm a Physician Scientist, a practicing Neuro-Oncologist, and at the time, I was in the laboratory trying to dissect out, why do children die from brain tumors. I was also taking care of children who were losing their battle. And so, a couple of years prior, I had been trying to figure out how to set up a postmortem or a research-based autopsy program. I knew from talking to some of my own families and helping to make it happen, it was really important and meaningful to them. But the logistics were beyond me as a single provider. You know, it really takes a lot of logistics going from the initial conversation, to how to make it happen. And so, one of my colleagues, Dr. Rishi Lulla, introduced me to Patti and Al. We realized we had a shared mission. And so, I've been very fortunate and grateful to be involved in this project. And, you know, including some of the comments from the paper, as well as meeting and talking with families, and seeing even the larger scope, families do want us to ask. This is meaningful for many families. And it's a really special moment for me as a provider in any of the autopsies that I help to c

Dr. Westin and Dr. Justin C. Brown discuss how physical activity can improve disease-free and overall survival in colorectal cancer and its potential application across all cancer types. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Westin: Hello, everybody, and welcome to another episode of JCO After Hours, the podcast where we get in depth on recent manuscripts published in the Journal of Clinical Oncology. And it is my great pleasure today to tell you we're going to be talking about a really important manuscript: "Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 Alliance Study." And this was published in the JCO on August 9th, 2022. All participants in the podcast have no conflicts of interest. And I am very excited to welcome the first author on this important paper, Dr. Justin C. Brown. He is the Director of the Cancer Metabolism Program and Assistant Professor in Cancer Energetics at the Pennington Biomedical Research Center at Louisiana State University. Welcome, Dr. Brown. Thank you for being here. Dr. Justin C. Brown: Thanks so much for having me. Dr. Westin: So, this is some really important work, and I think we're starting to see more and more really objective data around the importance of physical activities. But before we get too far down the road, I do want to level set because this was a study in colon cancer. So, just because we have a really mixed audience, give us a quick bit of information about the standard treatment for colon cancer and where we are with survival outcomes. Dr. Justin C. Brown: Yeah. So, for most patients with early colon cancer, they'll get upfront surgery. And then a subset of patients who have high-risk features for recurrence, or have positive lymph nodes or tumor deposits, will get three or six months of chemotherapy. And outcomes have improved over time for this population, but there is still a lot of heterogeneity, in that, some patients do better than others. And you know, a lot of patients ask as they finish therapy or as they're starting therapy, "Are there things I can do that potentially could improve my outcomes?" And so, we think that this data will provide physicians with a lot of really important information regarding the benefits of physical activity during chemotherapy, as well as after therapy, for patients with stage three colon cancer. Dr. Westin: Okay, that's great. And so, again, continuing on that level-setting piece, before this study, what did we know about the impact of physical activity on outcomes in colon cancer? Dr. Justin C. Brown: So, we knew that there was some association between physical activity during chemotherapy and after chemotherapy with disease-free survival and overall survival. There have been studies that have linked those two things. There was some uncertainty about, what is the best exercise or physical activity prescription? And so, a lot of the current recommendations before this study basically said encourage patients to avoid sedentary behavior, encourage them to be as active as they can be, because some activity provides benefits over no activity. But for the patient who really wanted the specifics of how much should I be doing, when should I be doing it, what types of activities should I be doing, should I avoid certain things, the evidence was really absent. And so, what this study provides is a lot of important clarity for both physicians and patients about the types of activities that can maximize their disease-free survival and overall survival. Dr. Westin: I think that's so important because you're exactly right. We all have those patients that you give them a vague, and they're like, "No, I need instructions. I need to know how much time. I need to know what I'm doing." And it can be really frustrating because—I know personally, I'm like, "Well, this is what I do." And I'm like, is that enough? I have no idea. So, this is really important work. And before we get into the specifics of the work, can you just give our listeners a little information? Do we know anything else about physical activity in other cancer types? Like, beyond colon cancer, is this something that's broad-based across everybody? Dr. Justin C. Brown: Yeah. So, there is emerging observational evidence that physical activity after diagnosis of early breast cancer, of early prostate cancer, is associated with improved disease outcomes, so disease-free survival, overall survival; that's observational data. We do have randomized clinical trial data on other quality of life endpoints and biologic endpoints in a variety of tumor types. And we know that patients who engage in physical activity or exercise during and after treatment tend to have better quality of life, they have less fatigue, they have improved physical functioning, they have reduced inflammation, improved insulin sensitivity. So, there's a variety of short, medium and potential long-term benefits to being physically active after your diagn

Shannon Westin, Francesca Gany, and Theresa Hastert discuss the topic of food insecurity among patients with cancer. TRANSCRIPT Dr. Shannon Westin: The guest on this podcast episode has no disclosures to declare. Hello friends and welcome to another episode of JCO After Hours, your podcast to get more in-depth on some of the amazing work that has been published in the Journal of Clinical Oncology. I am thrilled to be here today with two fantastic investigators and researchers who are going to discuss a paper that is titled "Food to Overcome Outcomes Disparities – A Randomized Control Trial of Food Insecurity Interventions to Improve Cancer Outcomes." This was published online in the JCO on June 16, 2022. We're joined by the principal investigator Dr. Francesca Gany, who is the Chief of Immigrant Health and Cancer Disparities service at the Memorial Sloan Kettering Cancer Center in New York City. In addition to Dr. Gany, we're also joined by Dr. Theresa Hastert, who's an associate professor in Population Science in the School of Medicine at Wayne State University in Detroit. And she published an editorial that went along with this article named "The Potential of Cancer Care Settings to Address Food Insecurity." This was published in the JCO on July 1st, 2022. Welcome, ladies. So excited to hear about this work. Dr. Francesca Gany: Thank you! It's great to be here. Dr. Theresa Hastert: Thanks so much for having me. Dr. Shannon Westin: So, what we're seeing more and more of is oncologists getting into other areas of expertise. For a long time, we've all been involved with treatment trials, and we've started getting into survivorship and health services. But I think that we really are realizing there are other issues for our patients that affect their cancer care and outcomes. So, first, I just wanted to level set and see if maybe Dr. Gany, you can kick us off, can you define food insecurity and just kind of briefly discuss the prevalence patterns in women and men that are diagnosed with cancer? Dr. Francesca Gany: Sure! So, food insecurity is essentially not enough access to food to help you maintain your health. And that could come from a variety of reasons, including not having enough money to buy food, living in a food desert, where there's not availability of food and other factors that could make food inaccessible to you. This potentially has a tremendous impact on health. We see that with folks with cancer and folks who don't have cancer. We know with cancer patients, it's a particularly difficult issue because of the increased nutritional demands that come with a cancer diagnosis, the need for special diets, and decreased absorption of nutrients for certain folks. So, it's especially important that our cancer patients have access to enough healthy food, so they can have the best cancer treatment outcomes possible. Dr. Theresa Hastert: I can add a little bit about the prevalence of food insecurity more broadly. So, in the US population, about 4% of Americans have what's called very low food security. So, that's where people actually reduce the amount of food they eat because they have a lack of money for food. And by contrast, in previous work among cancer survivors, that number is closer to about 15% in sort of population-based studies and much higher in certain select patient populations. So, if you're in an under-resourced population, and as some of Dr. Gany's previous work has cited figures of more like 55 to 70% of cancer patients and survivors with low resources can be food insecure and not have enough money for food. Dr. Francesca Gany: All of this has, of course, worsened with a COVID pandemic because just food insecurity rates have gone up overall and we have certainly seen an impact on our patients in the cancer centers in which we work. Dr. Shannon Westin: And you can imagine with the high costs of drug pricing and all of the other issues around coverage of cancer care that people are having to make those types of decisions between food and shelter and basics and getting their treatment for their cancer, their treatment for their other related comorbidities. Am I on the right track? Dr. Francesca Gany: Absolutely! In fact, we did a study that specifically asked patients whether they were not purchasing medications in order to be able to feed their families. And a very high percentage of them, up to a third of patients, said that they were foregoing some of their cancer meds in order to be able to feed their family. We asked it the opposite way as well, whether purchasing their cancer meds meant that they were unable to feed their families and unfortunately, it was a similar percentage for those food insecure patients. So, it has a tremendous impact on fully engaging in cancer treatment, and also being able to take care of one's family which of course is so important to our patients. Dr. Theresa Hastert: So, in Detroit, we're in Michigan, which expanded Medicaid. So, in the work that we do pred

Dr. Shannon Westin discusses the topic of climate change in the operating room with Dr. Anaeze Offodile and Dr. Elizabeth Yates. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hey everybody! Welcome back to JCO After Hours, a podcast where we get a little bit more intense, a little bit more specific about articles that are published in the Journal of Clinical Oncology. My name is Shannon Westin, and it is my honor to serve as the social media editor for the JCO. I'm an associate professor at the University of Texas MD Anderson Cancer Center and a gynecologic oncologist. Today, we are going to be discussing a really exciting paper which was published in the March online JCO. It's a Comments and Controversies piece called, "Prescriptions for Mitigating Climate Change-Related Externalities in Cancer Care: A Surgeon's Perspective." I have several guests with me today, none of whom have any conflict of interest. The first is Dr. Anaeze Offodile, who is an assistant professor in the Department of Plastic Surgery, as well as in the Department of Health Services Research at the University of Texas, MD Anderson Cancer Center. He also serves as the Executive Director of Clinical Transformation at MD Anderson. He is the senior author on the paper, so he will have a lot to offer here. But we're also accompanied by Dr. Elizabeth Yates, who has the title of clinical fellow in surgery at the Brigham and Women's Hospital in Boston, but tells me she's a rising PGY 4 resident, which makes it even more impressive that she is already published on the role of the surgeon in climate change. And so, we're so honored to have her with us today to share her perspectives as well. Welcome both of you. Thank you for being here. Dr. Anaeze Offodile: Happy to be here. Dr. Elizabeth Yates: Thanks so much for having us. Dr. Shannon Westin: So, I'm definitely someone that has been interested in climate change for some time, and living in the state of Texas, does what I can to rally the political climate here. But I was really intrigued because I never really thought of it in terms of what we do in the operating room. So, I'd love for each of you to give just a little bit of background on your careers and how you kind of got involved with this idea of climate change and environmental sustainability here in the operating room and in medical care? Do you want to start, Anaeze? Dr. Anaeze Offodile: Liz can start first. Dr. Elizabeth Yates: Absolutely! So, I actually came at it from an interesting perspective, I have always been interested in issues of resource distribution and disparities. And when I was in medical school, I started to think about these issues pretty deeply, especially because my younger brother was at the University of Michigan at the same time as I was, studying Environmental Science for his undergraduate and kept nagging in my ear about this problem of climate change and why I wasn't thinking about it as a doctor. And with my kind of ongoing interest in disparities, I came to realize and become compassionate about the role that climate change will play in driving the existing disparities that we see both nationally and globally. And I realized that nobody was really talking about it yet, at least in the surgical field. It had started to permeate some of the medicine and subspecialties, but really, there wasn't a conversation in our world yet. It became all the more relevant to me because I did see this dual relationship where not only do the downstream factors of climate change, like heat waves and major storms, impact our patients' access to care and their outcomes, but on the flip side, we contribute to climate change, because the delivery of surgical care, particularly in high-income countries, is so energy intensive and so wasteful. And so, I felt like if any clinician has a role in this space to really lead and change the narrative, it would be us as surgeons. Dr. Anaeze Offodile: It's really interesting to listen to Liz's journey to this issue, which affects all of us. I came at it from the micro level, bottom-up level. So, when I was a fellow about four years ago, under the mentorship of Nancy Perrier, we launched and have since scaled, I don't know if you're aware of this, Shannon, so the 'Know Your Costs' program. For the audience, this is a project at MD Anderson where we really try to minimize cost variability and waste in the operating room by providing a feedback tool to surgeons that sort of made them more conscious about the spending directly attributable to disposable supplies, implants, devices in the OR. One direct outcome of the project that we found was that actually narrowing the variability in these disposable instruments, supplies implants surely had no impact on the outcome, but also got sort of the cost structure of what we do in the OR down. So, that's the value-based care proposition. And in doing this work as I dug more into literature, I learned as

Shannon Westin, Veena Shankaran, and Scott Ramsey discuss the issue of financial toxicity among low- and middle-income cancer patients. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Westin: Welcome to JCO After Hours. I am your fearless leader, Shannon Westin, the editor for social media of the Journal of Clinical Oncology, and it's my great pleasure to bring you another episode. Today, we are going to be talking about a paper published in the January 7th version of the JCO called "Risk of Adverse Financial Events in Cancer Patients: Evidence From a Novel Linkage Between Cancer Registry and Credit Records." And none of the participants have any conflicts of interest. I am joined by two amazing people. First, let me introduce Dr. Veena Shankaran. She is a physician in the Seattle Cancer Care Alliance, professor in the Division of Medical Oncology at the University of Washington School of Medicine, and co-director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch Cancer Research Center. Hey, welcome. Dr. Shankaran: Hi, Shannon. Thanks for having me. Dr. Westin: I'm so excited to have you. And she's joined by her colleague, Dr. Scott Ramsey, who is a professor in the cancer prevention program in the Public Health Sciences Division at Fred Hutch and the director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch. Welcome, Dr. Ramsey. Dr. Ramsey: Shannon, great to be here. Dr. Westin: This is such an exciting paper and so very timely. We've been certainly hearing—I wouldn't say a lot but more and more about financial toxicity over the last few years, I'd say very appropriately. So, let's start with the basics. Let's make sure we level set. Can you educate our listeners on what financial toxicity is and what it means for patients with cancer? Dr. Shankaran: Yeah, absolutely. I can start. Financial toxicity, I think, is a relatively recently recognized complication, if you will, of cancer treatments. And really, I would say over the last decade or so, the literature has just sort of exploded describing kind of the various aspects of this big problem. I think one conceptual model that sort of helps me understand financial toxicity was developed by Robin Yabroff and Reggie Tucker-Seeley that really describes financial toxicity is that trifecta of material, financial hardship, kind of what we think of as out-of-pocket expenses, debt, the money that you pay to get cancer care. The other aspect is sort of the indirect coping mechanisms related to the cost of cancer care, like forgoing treatment, forgoing surveillance, cutting back on treatment-related cost concerns. So, more of the behavioral aspects. The final aspect is sort of the psychosocial-psychological aspect of financial hardship, which is really just the distress related to how am I going to pay for all of this? How is this going to affect my children and sort of our financial well-being? It's a big problem, a broad problem that touches on a variety of issues and also affects families and caregivers too. Dr. Ramsey: I would add that financial toxicity really got into the literature probably seven or eight years ago. The term itself was coined by an oncologist, Yousuf Zafar, at Duke University. He told me he actually heard it from a patient who, when he was describing all the toxicities of cancer treatments, the patient said, "Well, don't forget financial toxicity." And so, that's how the term, according to Yousuf, was coined. He published a series of case reports on patients who experienced financial toxicity. And our group did a study where we linked federal bankruptcy records to the cancer registry and found about a 65% higher risk of bankruptcy among cancer patients. We also did a subsequent paper looking at mortality among cancer patients who went bankrupt compared to cancer patients who did not and found excess mortality. So, we do have evidence that severe financial toxicity, i.e. bankruptcy can actually affect survival. And now, since that time, there have been other papers that have looked at quality of life, adherence to therapy and have found those as adverse impacts as well. Dr. Westin: Well, that makes sense when you're looking at that trifecta. I hadn't heard that. That was really educational for me. But looking at the ways that patients cope with this issue and actually foregoing their cancer treatment. And I think I've certainly heard about that in terms of like diabetics, like maybe taking their insulin every other day versus every day. You could see where we would see something similar in a patient with cancer. Do we have any data to know how common this is across our patients with cancer? Are there specific cancers where we see this more commonly, or is this kind of every cancer type is at risk? Dr. Shankaran: The non-adherence aspect? Yeah, I mean, I think in the studies that we've done, it hasn't been reported terribly commonly by patients. So, probably on the order

Shannon Westin and Virginia Sun discuss the JCO article "Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: A Multicenter Randomized Controlled Trial" TRANSCRIPT Speaker 1: The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello everyone. This is Dr. Shannon Westin, your JCO Social Media Editor here with another episode of Journal Clinical of Oncology After Hours Podcast. So excited to bring you in depth discussion on some of the amazing studies and manuscripts that have been published in the JCO. I am joined today by Dr. Virginia Sun, who's Associate Professor in the Division of Nursing Research and Education and the Department of Population Sciences Education at City of Hope. Dr. Shannon Westin: She has 17 years experiences as an oncology nurse, four years experience as a nurse practitioner, before becoming a full-time nurse scientist. And her research program is meant to develop and test interventions to improve patient and family-centered care and outcomes, specifically on cancer surgery and cancer survivorship populations. And what better person to have with us today as we're discussing the article, Patient Reported Outcome Based Symptom Management Versus Usual Care After Lung Cancer Surgery, a multi-center randomized control trial by Dr. Dye and colleagues. So welcome, Dr. Sun. So excited to chat with you today. Dr. Virginia Sun: Thank you so much for the opportunity to be here. Dr. Shannon Westin: So let's get right into it. I think this article caught several of the editors' attention, because it really is an exciting [inaudible 00:01:42] into how we might take care of patients after surgery. And as a surgeon myself, I was completely intrigued so I can't wait to get your perspective. So let's start off first, the author's note that patients with lung cancer have a high symptom burden after surgery, as a non lung cancer expert, can you walk those of us through a typical post op course and some of the issues that might be experienced by these patients? Dr. Virginia Sun: Sure. So, I think symptoms is something that probably all of our patients who just underwent surgery experience. But for our patients with lung cancer, some of the common symptoms would include pain. I think pain is one of those universal symptoms that many of our patients experience after a procedure. But particularly for this population, they would also experience shortness of breath, of course, because anatomically there were certain parts of their lung that were removed as part of the procedure. Dr. Virginia Sun: Cough is something that they would experience regularly as well. And I think sleep disturbance is one of those general symptoms that all of our patients may experience. And also just emotionally, the anxiety perhaps, and the stress may continue probably in the immediate post op timeframe when they just transition home. And then also the functional decline, also happening along with the fatigue. Many of our patients, although we get them up and out of bed as soon as possible, as a nurse, I know that's generally sort of our responsibility in the post-op recovery period. Certainly fatigue and the functional decline is something that our patients will experience in this population as well. Dr. Shannon Westin: Certainly many of those are universal across what we see in patients in the postoperative period. But I know personally, and I'm sure you could speak to this as well, we're busy post op, right? Especially whether you're rounding in the hospital, or you're seeing patients in post op in the clinic, I don't know how much we really get super deep dive into a lot of these symptoms. So I think that's what makes this work so important. So I'll just have you, if you could, briefly discuss this study design that was performed by Dr. Dye, and Dr. She, and their colleagues. Dr. Virginia Sun: Sure. So the intervention is really patient report outcome based symptom management. And this is done by way of alerts and completion of the MD Anderson Symptom Inventory, which is very well known symptom inventory tool well validated within this population as well. And also when patients share that information after surgery, and while they're recovering in the hospital, that will prompt an alert. So there were predetermined thresholds by way of the symptom score. So if a patient on the trial that reported a four to 10, which is generally a moderate to severe intensity for a symptom, and that will trigger an alert to the surgeon and the surgical team for management purposes. Dr. Virginia Sun: Now, in terms of this trial, the investigators chose several very relevant symptoms to focus on for this population to assess. And that would include pain, fatigue, cough, shortness of breath, and sleep disturbance, although the MD Anderson's Symptom Inventory does cover more of symptoms and beyond those as well. And in addition, I think, to the surgeons in response to the alerts

Dr. Shannon Westin and Dr. Antonio Di Meglio discuss the issue of fatigue among cancer survivors. Transcript [MUSIC PLAYING] Speaker 1: The guest on this podcast episode has no disclosures to declare. Shannon Westin (Dr. Westin): Hello, everyone. And welcome to another episode of JCO After Hours. This is our podcast where we get in depth with different authors and experts about wonderful manuscripts that are being published in the Journal of Clinical Oncology. And today it is my great pleasure to be accompanied by Dr. Antonio Di Meglio, who is a Medical Oncologist and a Physician Scientist at the Breast Cancer Survivorship Research Program in Gustave Roussy in France. So welcome, Dr. Di Meglio. Dr. Antonio Di Meglio (Dr. Di Meglio): Thank you so much for having me here today. Dr. Westin: We're so excited to have you. We're going to be talking about your article, which is due to be published January 21, 2022, in the Journal of Clinical Oncology titled "The Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care." And before we get started, I would just note that none of the guests have any relevant conflicts to disclose. With that, let's get into it. I was so excited to read this paper because this such a critical problem for our patients. And I'm a gynecologic oncologist, but this goes across all—surgical, medical, any field that we could even think of. So why don't you start off by telling us what led you to explore the problem of cancer-related fatigue? Dr. Di Meglio: Cancer related fatigue is one of the most troublesome and prevalent symptoms among cancer survivors and including breast cancer survivors. So several reports reported on the prevalence of cancer-related fatigue reporting up to 50% of patients in some studies with fatigue after cancer and the end of treatment. But what we know is that at least one in three cancer survivors experience fatigue symptoms at some point over time. In addition, we do know that fatigue is particularly distressing and impactful as it can impact on daily living and functioning and overall quality of life. Also, there's an important impact on social function and return to work after cancer and adherence to oral therapies, especially in the age event setting in breast cancer survivors. Finally, we also know that fatigue is often inadequately addressed and often neglected because of lack of time, lack of resources. Definitely, we should do more in the clinic for our patients struggling with fatigue. Dr. Westin: This is such an important issue. I think the elephant in the room here is how do we grade this and how do you advocate for a busy clinician in the clinic seeing 30, 40, 50 patients in a day. How do we really assess this? What's the best way to determine if somebody has cancer-related fatigue or is at risk? Dr. Di Meglio: Thank you for this important point. In clinical research, we do have a number of instruments that we can use to grade fatigue, including the European Organization For Research and Treatment of Cancer, Quality of Life Questionnaires that are the questionnaires that we used in our study. These are instruments that our patient reported. So we really can hear patient voices and patient perspectives in terms of their own symptoms. And some of the items that we use, for example, for cancer-related peak do not take much time to be asked also in a basic clinic. For example, we did use the EORTC QLQ Questionnaire C30 to score global fatigue. So we basically asked patient three questions: whether they needed to rest, they felt weak, or they felt tired, typical week. And these gave us the score of what we called global fatigue. There's also other instruments and companion models that we can use to assess more specifically dimensions of fatigue, including the physical, emotional, and cognitive dimension of fatigue. It is true that in our busy day in clinics, this may not be easily implementable. But what I believe is that if we never ask patients the right questions, patients will never tell us the right answers that we can proactively use to address the symptoms. So even just assessing fatigue in a general way, asking whether their energy levels changed over the past weeks, if they know that any change that was related to the treatment or any tiredness that was not really related to their usual activities or that was impactful on daily activities, this should trigger clinicians to ask more and more and to find solutions for the problem. So just ask the questions, even though the assessment may not be comprehensive and extensive, but this can be very important and meaningful for the patients. Dr. Westin: I think that's a really critical point because using validated instruments is obviously our aspirational goal and our attempted standard of care, but on a day in and day out clinic, it can be hard to have patients filling out a survey or something that may take a lon

Dr. Shannon Westin, Dr. Abby Rosenberg, and Dr. Reshma Jagsi discuss the timely issue of diversity, equity, and inclusion in the field of oncology. TRANSCRIPT [MUSIC PLAYING] SHANNON WESTIN: Hey, everyone and welcome to JCO After Hours, the podcast that gets a little bit more in-depth about some of the articles and amazing research that have been published in the Journal of Clinical Oncology. I'm so excited to be with you today. And more importantly, I'm very excited to talk about this amazing manuscript, which is called "Picture a Professional-- Rethinking Expectations of Medical Professionalism Through the Lens of Diversity, Equity, and Inclusion." And this was a Comments and Controversies article that was just published in October of 2021. And I am beyond thrilled to be joined by Dr. Abby Rosenberg, who was the lead author on this manuscript. And she is currently an associate professor in the Division of Hematology-Oncology, as well as in the Division of Bioethics and Palliative Care at the University of Washington School of Medicine. She has a number of different amazing accomplishments, including being the director of Palliative Care and Resilience Lab at the Seattle Children's Research Institute, the director of Pediatrics at the UW Cambia Palliative Care Center of Excellence, and the director of Survivorship and Outcomes Research in Pediatric Oncology at the University of Washington. In addition, she is our ASCO chair of our Ethics Committee. Welcome, Dr. Rosenberg. So excited to have you. ABBY ROSENBERG: Thanks for having me. Happy to be here. SHANNON WESTIN: And in addition to Dr. Rosenberg, we're also joined by one of her co-authors, Dr. Reshma Jagsi, who is the deputy chair of radiation oncology, the Newman Family Professor of Radiation Oncology, and the residency program director and the director of the Center for Bioethics and Social Sciences at the University of Michigan. You guys, we're going to spend this whole podcast just talking about how amazing the two of you are. Thank you so much for being here. RESHMA JAGSI: Thanks for having me. SHANNON WESTIN: So let's get into it. I'm really excited about this paper. I think it's super timely and certainly something that we've all been, I think, dealing with on a day-to-day basis and also reading about and really trying to get better at. So can you tell us a little bit-- and we'll start with you, Dr. Rosenberg-- about what first drew you to this work, how you got involved and, really, how you became passionate about it? ABBY ROSENBERG: Yeah, happy to. I think just, as you said, Dr. Westin, there is this ubiquity in the experiences, in particular of women and folks of color in medicine, where we feel discriminated against, and we feel like we don't belong. And we know from some really great data from the National Academies of Sciences that 50% of women in med school, for example, experience discrimination before they graduate. And when we educate them about what microaggressive and sexist behaviors can actually look like, that number goes way up. And most women, in particular, say that they're willing to, quote, "pay this price" for being in medicine because they believe in the work, and they believe in the mission. And for me, this was really personal. Because I was one of those people, too, until I got to the point in my career where I noticed how my mentees and people who reported to me were being held back. And that, to me, made me feel like there was something I really needed to do now as an advocate and mentor to try to change the system so that more women and people of color could be successful in our field. SHANNON WESTIN: That's great. And then how did you get involved Dr. Jagsi? I'd love to know how the collaboration came about and also about your passion for this work. RESHMA JAGSI: Thank you. Yes, so both Dr. Rosenberg and I have had the privilege of chairing ASCO's Ethics Committee. And I think, to both of us, this is a fundamental matter of professional ethics. And there's really two reasons that this is so centrally and fundamentally an ethical issue. And so one of them is that human beings have a duty to resect the dignity of other human beings. And this is a situation in which we are not treating one another with due dignity. And then, of course, there's also really important consequences when we do fail in that duty. And so it's important because we share a professional mission here to promote the highest quality of patient care, to educate those who are following in our field, and to do the scholarly research to discover advances that will ultimately benefit patients and society in the future. And all of those missions are enriched when we have a diverse workforce. So this is really squarely in the lane of ethics. And so when Dr. Rosenberg proposed this article, I was just more than delighted to be included in this work. SHANNON WESTIN: And it's so important for us, as women. And I am not a woman of color, but especially as we cr

Dr. Shannon Westin, Dr. Michael Gnant, and Dr. Kathy Miller discuss the results of the PALLAS trial.

Dr. Shannon Westin, Dr. Kirsten Beyer and Dr. Jennifer Griggs discuss how mortgage lending bias and residential segregation intersect with cancer disparities and survival outcomes. TRANSCRIPT [MUSIC PLAYING] SHANNON WESTIN: Hello, everyone. My name is Shannon Westin, and I'm an Associate Professor at the University of Texas MD Anderson Cancer Center in the Department of Gynecologic Oncology and Reproductive Medicine. And I currently serve as the Social Media Editor for the Journal of Clinical Oncology. And we're starting a brand new podcast series to try to bring really exciting research that's being published in the JCO to you, and I'm so excited to kick off this series with a group of very accomplished women who are covering something that I don't think a lot of us don't know very much about. So I'm really excited to learn a ton over this next few minutes. So it's my pleasure to introduce Dr. Kirsten Beyer, who is an Associate Professor in the Division of Epidemiology in the Institute for Health and Equity as well as the Director of the PhD program in Public and Community Health at the Medical College of Wisconsin. We are also joined by Dr. Jennifer Griggs, who's a Professor the Department of Internal Medicine, Division of Hematology Oncology, as well as a member of the Institute of Health Care Policy and Innovation at the University of Michigan. She does predominantly practice taking care of women with breast cancer. Welcome, doctors. JENNIFER GRIGGS: Thank you. KIRSTEN BEYER: Thank you very much. SHANNON WESTIN: So we're talking today about the manuscript "Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States" that Dr. Beyer published just this month in the JCO. In addition, Dr. Griggs and her colleague Dr. Pleasant were invited to participate in an editorial called "Contemporary Residential Segregation and Cancer Disparities." So let's get into to what was covered. So I think for me, the lowest hanging fruit here, Dr. Beyer, is understanding what exactly is redlining, because that was one of the critical exposure that you were assessing amongst these women with breast cancer. KIRSTEN BEYER: Thank you, Dr. Westin. Yes, redlining-- I think most people think about redlining as being a historical practice, where mortgage lenders would essentially draw red lines around particular neighborhoods and then not lend mortgages in those areas, regardless of whether or not the applicant for that mortgage was otherwise qualified. So it's generally thought of as a historical practice. But what we've done in this study is to look at some more contemporary data and create a new measure that we think represents contemporary redlining, maybe not in the legal sense in terms of housing discrimination. But this measure represents essentially the odds ratio of denial of a mortgage application for a property in a local neighborhood as compared to the metropolitan area as a whole. So we're really looking to see which areas of our US cities are systematically denied mortgage applications. By denying those mortgage applications, they are suffering from disinvestment, and I would argue structural racism is guiding a lot of that practice. SHANNON WESTIN: So can you explore that a little bit more with us? And how do you find that type of data? Where do you get this information about these denied mortgages? How do you get into the different covariates like race, ethnicity, things like that? KIRSTEN BEYER: Sure. So I think a little history lesson is important first. Between the historic practice of redlining and today, there have been a number of major laws that have been passed in the United States really to try to overcome housing discrimination. Some of the most important ones are-- in the Civil Rights Act of 1968, there was something called the Fair Housing Act, and that act prohibited discrimination in the sale, rental, and financing of housing based on race, religion, and national origin. And since then, they've added a few more protected categories. And then right after the Civil Rights Act of 1968, there was something passed called the Home Mortgage Disclosure Act. And this act was essentially to bring transparency to mortgage lending in this country. The idea was that we were requiring public disclosure of loan-level information about mortgages that were lent in the country. And the goal was to shed light on lending patterns, including those that could be discriminatory. And so the HMDA data-- it's commonly referred to as "hum-duh." That HMDA data has been collected then since 1975. And that database evolves over time, but we use that data for 2007 to '13 to really try to understand what are the mortgage lending patterns in our US cities in terms of their spatial distribution. And so there are a number of covariates that we were able to control for there. There are some things that we're not able to control for. I'm excited that the HMDA database has recently improved, and there are some new

This podcast will discuss data from a phase II trial evaluating the dose-adjusted EOPCH-R chemo-immunotherapy regimen for the treatment of primary mediastinal B-cell lymphoma in children. TRANSCRIPT [MUSIC PLAYING] LISA GIULINO-ROTH: This JCO podcast provides observations and commentary on the JCO article "Dose-Adjusted Rituximab Therapy in Children and Adolescents with Primary Mediastinal B-cell Lymphoma, a Multicenter Phase II Trial" by Burke et al. My name is Lisa Giulino-Roth, and I am a pediatric oncologist at Weill Cornell Medical College in New York. My oncology specialty is lymphoma in children, adolescents, and young adults. I have no relevant disclosures. Primary mediastinal B-cell lymphoma, or PMBCL, is an aggressive non-Hodgkin lymphoma derived from thymic B-cells. While previously classified as a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as a distinct clinical and pathologic entity. Unlike diffuse large B-cell lymphoma, PMBCL has a peak incidence among adolescents and young adults and is more common in females. PMBCL also shares many molecular characteristics with Hodgkin lymphoma, including alterations in JAK-STAT pathway signaling and amplification of the 9p24.1 locus, leading to upregulation of PD-L1. Adults with PMBCL have historically been treated on regimens designed for diffuse large B-cell lymphoma, which in the US was most commonly R-CHOP and radiation therapy. More recently, adult patients have been treated with a dose-adjusted EPOCH-R regimen, which is composed of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab. This radiation-free approach is of interest, given this young and predominantly female population who are at risk for significant long-term toxicity from chest radiation. In a single center NCI-led study by Dunleavy and colleagues, dose-adjusted EPOCH-R was administered for six to eight cycles without radiation therapy and resulted in excellent outcomes with a five-year event free survival of 93% and overall survival of 97% among 51 adult patients. Pediatric patients with PMBCL have historically been treated on regimens designed for mature B non-Hodgkin lymphoma, which in pediatrics is most commonly Burkitt lymphoma or diffuse large B-cell lymphoma. These dose intensive multi-agent regimens include doxorubicin, high dose methotrexate, and intrathecal chemotherapy without radiation. Outcomes for children with PMBCL treated on these regimens are inferior to pediatric patients with diffuse large B-cell lymphoma treated on the same protocol. Children with PMBCL have a five-year event-free survival ranging from 65% to 75% in different international series. Given the excellent outcomes observed with dose-adjusted EPOCH-R in the adult NCI trial, an international phase II trial of this approach was conducted by two cooperative groups, The European Intergroup for Childhood Non-Hodgkin Lymphoma and the Children's Oncology Group. This single arm trial enrolled patients age 18 and under with primary mediastinal B-cell lymphoma. All patients were treated with six cycles of dose-adjusted EPOCH-R without radiation. The primary endpoint was event-free survival with events defined as any of the following-- viable cells in any residual mass after six cycles of treatment, relapse, progressive disease, secondary malignancy, or death from any cause. The four-year event-free survival from this trial would be compared with the event-free survival from historic controls, which was estimated at 67%. A total of 46 pediatric patients were enrolled between 2012 and 2016. All patients received six cycles of dose-adjusted EPOCH-R without RT. At a median follow-up of 59 months, there were 14 events, including four patients with viable cells in the residual mass at the completion of therapy, eight progressions or relapses, and two secondary malignancies, including one case of Hodgkin lymphoma and one case of acute promyelocytic leukemia. The event-free survival of the entire cohort at four years was disappointing at 69.6% with a 95% confidence interval of 55.2% to 80.9%. This was not statistically different than historic controls treated on pediatric mature B and HL regimens. Overall survival at four years was 84.8% with a 95% confidence interval of 71.8% to 92.4%. The authors acknowledge several limitations in the current study and challenges when comparing this study to the NCI trial. Not all patients adhered to the dose escalation rules, and 29% should have received a higher dose level in at least one course of treatment. Among the 10 cases of local relapse or primary refractory disease, five were noted to have a failure to dose escalate, including one patient with a clinical complication that precluded dose escalation. Comparing this trial to the NCI trial is challenging due to several important differences. Adults in the NCI trial were treated with six or eight cycles of dose-adjusted EPOCH-R based on the response between cy

This podcast discusses the study, steroid dose reduction, practice experience, and guidance changes. TRANSCRIPT [MUSIC PLAYING] ROBIN ZON: This JCO podcast provides observations and commentary on the JCO article-- "Do Steroids Matter: A Retrospective Review of Pre-Medication for Taxane Chemotherapy and Hypersensitivity Reactions," by Lansinger et al. My name is Dr. Robin Zon. And I am the quality oncology practice initiative lead physician for Michiana Hematology Oncology, an independent community oncology practice located in Mishawaka, Indiana. My oncologic specialty is general medical oncology. And I have a strong interest in breast cancer. This article is based on the premise that there exists significant variation regarding the prescribing practices of steroids for pre-medication to minimize the known hypersensitivity reactions associated with the taxanes paclitaxel and docetaxel. In fact, the authors remind the reader that initial clinical development of paclitaxel was delayed due to the notable hypersensitivity rate of 25% to 30%, as patients did not receive pre-medication. Subsequent trials used a pre-medication strategy of dexamethasone, diphenhydramine, and H2 antagonist, with a reduction of the reaction occurrence to 2% to 3%. As a result of the improved reaction rates in clinical trials with the use of a pre-medication regimen, both paclitaxel and docetaxel, FDA approved package inserts recommend oral corticosteroid pre-medication, 20 milligrams, 12 and 6 hours prior to the taxane administration. However, there has been no dose optimization to date. In fact, the authors note that lower dose regimens are routinely used in daily practice and may lead to increased risk of hypersensitivity reactions. Furthermore, steroids can cause multiple adverse effects if taken for extended periods of time, which can range from mild to moderate in their severity. This study reviewed steroid prescribing patterns in patients receiving the first dose of paclitaxel or docetaxel at Stanford Cancer Institute between 2010 and 2020. A total of 3,181 patients met criteria for analysis, with an 8.3% rate of hypersensitivity reactions. And the adjusted multivariate analysis, the authors found no correlation between the hypersensitivity reaction rate or the severity among the variables evaluated, except for the gynecology/oncology clinic patients who had an increased risk for hypersensitivity reactions overall with a hazard ratio of 1.34 and high grade hypersensitivity reactions with a hazard ratio of 2.34, and female patients who had a higher rate of hypersensitivity reactions overall with a hazard ratio of 1.26, but not high grade hypersensitivity reactions. The conclusion of the article is that neither dexamethasone dose nor route, IV or oral, correlated with subsequent hypersensitivity reactions. And that the recommended 40 milligrams dose of dexamethasone prior to taxane administration is no better than the 10 milligrams dose for protecting against hypersensitivity reactions. Therefore, the lower doses used in clinical practice is acceptable and even preferable to higher doses. Although the study authors point out that the strength of the study is the large data set reviewed, they also point out that this study was a retrospective analysis completed on first dose dexamethasone use and not on subsequent taxane exposures Additionally, the authors also point out that since there was no external validity, the results may not be generalizable to other patient populations treated at other institutions. For the remainder of this podcast, the commentary represents my opinion only and may not represent the opinion of this journal or its editors. First, I would like to commend the authors on this analysis, which addresses a very practical question-- do steroids matter. And is it possible to safely vary from the package insert? The work dedicated to collecting this data set does not go unnoticed. As the authors acknowledge, the prescribing practice patterns for steroid pre-medication does vary considerably across and within practices. Furthermore, the common references that practices use for treatment guidance, including NCCN and UpToDate, describe differing options. For example, the NCCN order template for weekly paclitaxel refers to using pre-medication of H2 blocker plus diphenhydramine and dexamethasone 10 milligrams IV with weekly doses, one to three, then may consider dose reduction of dexamethasone to 4 milligrams with weekly dose 4, and does not elaborate on further dose reduction. For Q2 or three-week paclitaxel dosing, the NCCN template follows the package insert. UpToDate also recommends 20 milligrams of dexamethasone orally 12 and 6 hours prior to drug administration with H1 and H2 receptor antagonists as a pre-medication regimen for Q2 or three-week treatment. However, for weekly paclitaxel, UpToDate offers consideration of a dexamethasone dose of 10 milligrams IV with H1 and H2 blockers, then tapering the glucocortic

Improving care in vulvar cancer via the prospective Vulvar GROINSS VII study TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients with Micrometastases in the Sentinel Node: Results of GROINSS-V II" by Oonk et al. My name is David Gaffney, and I am a professor and Vice Chair of Radiation Oncology at the University of Utah. I am also Senior Director for Clinical Research at the Huntsman Cancer Institute in Salt Lake City, Utah. My oncologic specialty is radiation oncology. I have no relevant disclosures to this study. The GROINS VII study is the successor trial of the GROINS V I trial. In the GROINSS-V I study, the authors demonstrated that omission of an inguinal femoral lymphadenectomy was safe in patients with a negative sentinel lymph node with an isolated GROIN recurrence rate of 2.3%. It also showed that with long term follow up a significant proportion of patients will recur. At 10 years local recurrence occurred in 39.5% of all patients. Although local recurrences are treated with curative intent, the disease-specific survival of these patients decreases significantly. It is important to ask if there is a dose response to radiotherapy in vulvar cancer? GOG 101 was published in 1998 and employed a split course of radiotherapy to a dose of 47.6 Gy with concurrent cisplatin and 5-FU. The complete response rate was 46.5%. The subsequent prospective phase II randomized trial, GOG 205, was published in 2012 and employed 10 Gy more of radiotherapy with weekly cisplatin to a total dose of 57.6 Gy. This study demonstrated a 78% pathologic complete response rate. Hence, by adding 10 Gy, the complete response rate increased by 30%, indicating a steep dose response. Also, by way of background, a retrospective study from MD Anderson by Stecklein et al. published in 2018 demonstrated a 3-year actuarial groin control rate of 83% with high dose conformal radiotherapy with a median dose of 66 Gy to grossly positive nodes. These data demonstrate that radiotherapy can sterilize gross disease in select circumstances. The GROINSS-V II study was a phase II prospective study in a rare disease, and sought to answer whether radiotherapy to 50 Gy could be an effective and less morbid alternative to inguinofemoral lymphadenctomy Patients were accrued from 59 hospitals in 11 countries. Eligibility for this study were patients with tumors less than 4 cm, with negative groin nodes on preoperative CT, MRI, or ultrasound. The primary endpoint was a groin recurrence rate at 24 months. A combined technique was used to evaluate the sentinel lymph node of lymphoscintigram and blue dye. Bilateral sentinel lymph node procedures were required for midline lesions. The radiotherapy was 50 Gy in 25-28 fractions with the field size to extend to the bottom of the SI joints, including the distal external iliac lymph nodes. Greater than 1700 patients were registered. One hundred sixty patients were found to have micrometastases, that is disease less than 2 mm, whereas 162 patients were found to have macrometastases. The median size vulvar lesion for patients with negative sentinel lymph node was 18 mm, 23 mm for patients with micrometastases, and 25 mm for patients with macrometastases. Results at 2 years demonstrated an isolated groin recurrence rate occurred in 1.6% of patients that were treated per protocol with micrometastases. Whereas patients with macrometastases had an isolated groin recurrence rate at 2 years of 12.2%. For patients with macrometastases treated with radiotherapy, the groin recurrence rate was 22%. Whereas groin failure was 6.9% for patients who had macrometastases treated with inguinal femoral lymphadenectomy and radiotherapy. For patients with macrometastases, no groin recurrences were observed in 7 patients treated with chemoradiotherapy. Among the 1213 patients with a negative sentinel lymph node, an isolated groin recurrence occurred in 31 patients for a rate of 2.7% at 2 years. For the 56 patients who suffered a groin recurrence, 31 of them died of vulvar cancer for an overall survival rate of 39% at 2 years. This trial also looked at morbidity of patients treated with inguinal femoral lymphadenectomy versus sentinel lymph node procedure plus radiotherapy. The lower extremity edema rate was 32% at 6 months versus half of that for patients treated with the sentinel lymph node procedure plus radiotherapy. It should be noted that IMRT was utilized in 19% of cases, and chemotherapy was utilized in 12% of cases. This trial clearly demonstrated that in patients with a macrometastasis or disease greater than 2 mm within a groin node, radiotherapy is not a safe alternative to inguinal femoral lymphadenectomy due to a higher rate of groin recurrence, albeit there was no difference in disease-specific survival. Management of patients with vulvar cancer is complex. Clinicians need to control the ipsilateral

Dr. Lindsay Morton of the National Cancer Institute at the National Institutes of Health reflects on research findings by Øvlisen et al that leverage large-scale linked registries in Denmark to suggest that improvements in both chemotherapy treatments and assisted reproductive technologies have made it possible for more survivors of Hodgkin lymphoma to become parents. TRANSCRIPT This JCO podcast provides observations and commentary on the JCO article "Rates and Use of Assisted Reproduction Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study of 793 Patients and 3965 Matched Comparators" by Øvlisen and colleagues. My name is Lindsay Morton, and I am a Senior Investigator and Deputy Chief of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. I am trained in epidemiology, and my oncologic specialty is in hematologic malignancies and cancer survivorship research. I have no relevant conflicts to disclose. The adverse effects of treatment among patients with Hodgkin lymphoma have long been at the forefront of oncology research. In the late 1960s, patients with Hodgkin lymphoma were some of the first to receive combination chemotherapy with a four-drug regimen called "MOPP," consisting of mechlorethamine, vincristine, procarbazine, and prednisone. MOPP resulted in dramatic improvements in patient outcomes following diagnosis with Hodgkin lymphoma. But in subsequent decades, the toxicities of MOPP came to be understood, including both acute toxicities – most notably myelosuppression – as well as longer-term toxicities such as second cancers and sterility, especially in males. Around the same timeframe, long-term toxicities of radiotherapy also were increasingly recognized, which set off a search for effective Hodgkin lymphoma treatment approaches with fewer short- and long-term toxicities. I often think of how research on adverse effects in patients with Hodgkin lymphoma has been at the vanguard in cancer survivorship: this focus has helped to drive development of new therapies and changes in clinical practice. This has occurred in part because Hodgkin lymphoma is frequently diagnosed in early adulthood and patients now have such a good prognosis; this means there is a longer window in which to experience any long-term effects of cancer treatments, and patients face unique issues, such as impacts on fertility, which aren't relevant for older cancer patients. In the paper accompanying this podcast, Øvlisen and colleagues present novel data on parenthood rates and use of assisted reproduction techniques in Danish patients with Hodgkin lymphoma. Importantly, the results of this study are very relevant to current patients because all the patients in the study were treated between 2000 and 2015 using standard treatment approaches that are still frequently used today. About one-third of the study population received radiotherapy plus 2-4 cycles of the combination chemotherapy regimen called "ABVD," which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine, and is the preferred front-line therapy approach for Hodgkin lymphoma patients in the United States. Another third of the study population received 6-8 cycles of ABVD, while in the remaining third, about half received either "BEACOPP" (a seven-drug regimen, which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, and which is commonly used in Europe) or some other chemotherapy regimen. In this study, the authors compared the rates of parenthood in patients with Hodgkin lymphoma to individuals in the general population who were matched to the patients by age, sex, and parenthood status. Overall, the news was good: both male and female survivors of Hodgkin lymphoma had similar parenthood rates as the matched individuals from the general population. But the details of this bigger picture finding are really worth understanding because of their important impact on patients. In particular, a larger number of patients with Hodgkin lymphoma than the comparison individuals from the general population used assisted reproductive technology in order to become parents. Specifically, nearly 22% of male and 14% of female survivors of Hodgkin lymphoma used assisted reproductive technology compared with only about 6% of those in the general population. When the authors looked at various predictors of parenthood in subgroup analyses, one other finding stood out: male survivors of Hodgkin lymphoma who had received BEACOPP therapy had about half the rate of parenthood compared with other Hodgkin lymphoma survivors and the general population. In contrast, for female survivors, parenthood rates were similar among the different treatment groups, but the numbers of female survivors treated with BEACOPP was small, so we should be cautious about drawing conclusions f

This podcast describes the findings from a population-based retrospective decedent cohort study which suggest that palliative care involvement may be associated with a decreased need for high intensity of care during the final weeks of life in adolescents and young adults with cancer. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Impact of Palliative Care Involvement on End-of-Life Care Patterns Among Adolescents and Young Adults with Cancer: A Population-Based Cohort Study" by Kassam et al. My name is Erica Kaye, and I am Director of the Quality of Life and Palliative Care Research Division at St. Jude Children's Research Hospital in Memphis, Tennessee, USA. My oncologic specialty is pediatric palliative oncology. In this paper, the authors aim to evaluate the prevalence and predictors of high-intensity end-of-life care in adolescents and young adults with cancer in Ontario, Canada, as well as assess the impact of palliative care involvement on intensity of care received at end of life. This topic is timely and important. Growing evidence demonstrates that adolescents and young adults with cancer, defined by the National Cancer Institute as patients diagnosed between the ages of 15 and 39, face a unique set of circumstances that may adversely impact their end-of-life experiences. Several single-institution studies in the U.S. have suggested that adolescents and young adults with advanced cancer disproportionately receive high intensity medical care in their final month of life compared to children or older adults, and these findings recently have been replicated in population-level studies in California and New York. These observations raise concerns about exposure of a vulnerable population to toxicity from high intensity care at a time when such interventions are less likely to offer meaningful benefit. However, these studies had several notable limitations: some involved only insured patients; others presented data only from inpatient end-of-life care; and none evaluated the impact of palliative care provision on the intensity of end-of-life care for adolescents and young adults with cancer. Moreover, findings from U.S.-centric data sets may not be generalizable to other countries. In this study, the authors assembled a retrospective decedent cohort of adolescents and young adults with cancer who died between 2000 and 2017 in Ontario, Canada using a provincial registry linked to population-based health-care data. Predicated on previously published validated metrics, they used a primary composite measure for high-intensity end-of-life care that included receipt of intravenous chemotherapy less than 14 days from death; more than one emergency department visit; and more than one hospitalization or intensive care unit admission less than 30 days from death. Secondary outcomes included measures of the most intensive end-of-life care, such as intensive care unit admission within 30 days of death, mechanical ventilation within 14 days of death, and death in the ICU, as well as palliative care physician involvement. Predictors of outcomes were determined using regression models. In a cohort of more than 7,000 adolescents and young adults with cancer across Ontario, authors found that approximately 44% experienced high-intensity end-of-life care – double the rate for adults and slightly higher than the rate for children in the region. This percentage is lower than that seen in single-site and population-level studies in the U.S., however lack of consistently defined high-intensity end-of-life indicators for adolescents and young adults with cancer make it challenging to compare findings across studies. Importantly, adolescents and young adults with hematologic malignancies were at highest risk for receipt of high-intensity care at the end of life in Ontario, affirming findings seen across pediatric and adult populations in different countries. Some hypothesize that unique pathologies specific to hematologic malignancies may increase the risk of experiencing higher intensity end-of-life care. For example, a patient with refractory leukemia often requires frequent blood transfusions to prolong life and optimize quality time; this can be challenging to coordinate in the outpatient setting and may necessitate inpatient hospitalizations at the end of life. In both the U.S. and Canada, continuation of transfusion support often precludes hospice enrollment, further preventing patients from receipt of subspecialty palliative care in the home. In this context, legislation to support concurrent provision of palliative and hospice care with cancer-directed therapy may have the potential to mitigate high-intensity end-of-life experiences for this vulnerable patient population. This study also found that palliative care physician involvement substantially reduced the odds of adolescents and young adults with cancer receiving high-intensity end-of-life care, including the most intensive

Minimal residual disease positivity is predictive of disease progression in patients with large B-cell lymphoma treated with anti-CD19 CAR T-cells. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial' by Frank et al. My name is Patrick Reagan, and I am an Assistant Professor of Medicine at the Wilmot Cancer Institute, University of Rochester in Rochester, NY. My oncologic specialties are lymphoma and cellular therapy. I would like to disclose consultancy for Kite Pharma. Frank and colleagues present data from a prospective, multicenter trial examining serial testing of circulating tumor DNA in 72 patients with large B-cell lymphoma who received treatment with the anti-CD19 CAR T-cell, axicabtagene ciloleucel, abbreviated as axi-cel. These patients had circulating tumor DNA monitored in plasma prior to lymphodepletion chemotherapy, as well as at multiple times following axi-cel infusion. Ninety-six percent of patients had adequate DNA to identify a clonotype to track over time at study enrollment, and 60 patients had an adequate sample for analysis at day 28 after axi-cel infusion. There are several key findings in this study. The first key finding is that circulating tumor DNA may serve as a surrogate for tumor burden. A lower level of circulating tumor DNA was associated with both improved disease and toxicity outcomes. Patients who had a lower baseline circulating tumor DNA had improved progression-free and overall survival, as well as less severe cytokine release syndrome and immune effector cell associated neurotoxicity syndrome. A second key finding of this study is that circulating tumor DNA can serve as a marker for minimal residual disease in large B-cell lymphoma patients treated with CAR T-cells, and can be predictive of disease relapse. Seventy percent of patients who had durable response were negative for circulating tumor DNA one week following CAR T infusion. All patients with disease progression had at least one sample that was positive for minimal residual disease, and all but one were positive for minimal residual disease concurrently with radiographic progression. At day 28-post CAR T-cell treatment, negativity for minimal residual disease by circulating tumor DNA was strongly associated with improved progression-free and overall survival. A third key finding in this study was that positivity for minimal residual disease was highly predictive in patients who have a partial response or stable disease at day 28-post CAR T-cell treatment. Deepening of response over time has been reported with various CAR T-cell treatments suggesting that there are limitations of PET CT to assess response, particularly at early time points. In the patients who had stable disease or partial response who were positive for minimal residual disease at day 28 following axi-cel, 15 of 17 patients had a progression-free survival event, while only two of ten who were negative for minimal residual disease had a progression-free survival event. This study has multiple implications for future clinical research, which may influence routine clinical care over time. High tumor burden defined by the sum of product diameters or metabolic tumor volume has been associated with both treatment failure and excess toxicity with axi-cel, as well as tisagenlecleucel. As a potential surrogate for tumor burden, baseline circulating tumor DNA could be useful in determining high-risk groups to target for clinical trial participation. Additionally, this could be a stratification factor for randomized studies involving CAR T-cells. Additional studies with axi-cel as well as tisagenlecleucel and lisocabtagene maraleucel, which are also commercially available for large B-cell lymphoma, are important to confirm this observation. Management of patients who initially achieve a partial response or have stable disease at the first disease assessment is a common clinical problem in patients with large B-cell lymphoma treated with CAR T-cells. A proportion of patients with large B-cell lymphoma who initially have partial response or stable disease will go on to develop a complete response over time. This has been reported in all of the commercially available anti-CD19 CAR T-cell products. In the ZUMA-1, JULIET and TRANSCEND trials, approximately one third to one half of patients who initially had partial response or stable disease went on to achieve a complete response. Patients who ultimately have progressive disease have poor outcomes with a median overall survival of 180 days. Those who have stable or progressive disease as best response have a medial overall survival of only approximately 50 days. Predicting which patients are at risk to relapse is important given the small window of time to intervene. It would also potentially spare low r

Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia" by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King's College London and Consultant Hematologist at Guy's Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie. The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question. In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML. Karol and colleagues from St. Jude's Children's Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%. In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%. The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%. The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively. Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeare

This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation" by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy. For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body's immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well. Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used 'antigen-level' serological testing. However, with advances in technology, the field has moved on to 'allele-level' or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care. Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients. To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details. There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to b

The PENELOPE-B phase III trial did not show a benefit to the addition of one year of the CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in patients with hormone receptor-positive/HER2-negative breast cancer and residual disease after neoadjuvant chemotherapy. TRANSCRIPT This JCO podcast provides observations and commentary on the JCO article "Palbociclib for Residual High-Risk Invasive Hormone Receptor-positive, HER2 negative Early Breast Cancer – The PENELOPE-B Trial," by Sybille Loibl and colleagues. My name is Erica Mayer, and I am a clinical investigator at the Dana-Farber Cancer Institute in Boston, MA who specializes in breast cancer. Since the initial approval of the CDK4/6 inhibitor palbociclib in 2015, this class of agents has become a standard part of management for most patients with hormone receptor positive HER2 negative advanced breast cancer. Use of one of the available CDK4/6 inhibitors - palbociclib, abemaciclib, or ribociclib - in combination with endocrine therapy, improves progression-free, and even overall survival, in the advanced disease setting, as shown in the respective trial series PALOMA, MONARCH, or MONALEESA. Although differentiated by their toxicity profiles, with palbociclib and ribociclib contributing more neutropenia and abemaciclib more diarrhea, across-the-board the benefit gained from use of these agents is remarkably preserved between trials, without apparent differential drug activity. Following the observation of benefit from use of CDK 4/6 inhibitors in the advanced setting, clinical trials evaluating the three available agents were subsequently launched to evaluate these agents in the adjuvant setting, after prior treatment with surgery, chemotherapy, and radiation if necessary. The first two trials to report in 2020, PALLAS and MONARCH-E, enrolled patients with early hormone receptor positive HER2- breast cancer, randomizing them to receive a CDK 4/6 inhibitor, palbociclib or abemaciclib respectively, for a planned 2-year duration, in addition to ongoing adjuvant endocrine therapy, versus ongoing adjuvant endocrine therapy alone. Notably, PALLAS enrolled patients with stage II and III breast cancer, whereas MONARCH-E targeted a high-risk group identified by tumor size, nodes, and Ki67 status. Initial reports from these trials were presented at an interim follow-up of about 20-24 months, a time when many were still receiving the combination therapy. The MONARCH-E analysis demonstrated a benefit from the addition of abemaciclib to endocrine therapy in prolonging invasive disease-free survival. This benefit was not observed with the addition of palbociclib in the PALLAS trial. The ongoing NATALEE trial, offering 3-years of reduced dose ribociclib in a similar setting, continues accrual. It is within this context that we place the PENELOPE-B trial. This trial enrolled the highest risk patients with early HR+/HER2- breast cancer: those with residual disease after preoperative chemotherapy and a high CPS-EG score, which is a calculation of anatomic stage and tumor biology meant to identify patients at highest risk of cancer recurrence. A total of 1250 patients were randomized to receive either one year of adjuvant palbociclib with ongoing adjuvant endocrine therapy, or placebo with endocrine therapy, and followed for a primary endpoint of invasive disease-free survival. As expected, the study enrolled a very high-risk population, with many patients having at least T2 disease and 4 involved lymph nodes at time of surgery. At a median follow-up of 43 months, no difference in invasive disease-free survival was observed, with a 4-year iDFS of 73% in the intervention arm, versus 72.4% in the placebo arm. No clinicopathologic subgroup appeared to derive benefit from the research intervention. The toxicity experience was similar to that seen in the metastatic setting, with notable and expected hematologic toxicity, but no significant difference in overall non-hematologic adverse events. Overall, drug exposure was satisfactory, with about 17% of patients unable to complete the planned 1-year duration of therapy. The PENELOPE-B study makes its mark in the adjuvant CDK4/6 landscape in several important ways. First, PENELOPE-B has the greatest duration of follow-up, allowing analysis of mature data and outcomes during and following adjuvant CDK4/6 inhibition. Although it is tempting to interpret a slight visual divergence of the Kaplan Meyer curves during the palbociclib exposure, where there is an absolute difference in iDFS of 4.3% at 2 years, there is no statistical evidence that the 2-year iDFS estimates are different between the two arms, and therefore no evidence of time-dependent efficacy. Importantly, in regard to experiences within the other CDK4/6 inhibitor trials, which have reported at an earlier time point, longer-term follow-up of those trials will be necessary to determine stability and maturity of the observed results. Additionally, PENELOPE-B is the onl

Current clinical characteristics and demographics are not sufficient to capture aggressive disease in clinical trials of newly diagnosed DLBCL. Novel tools, such as measurement of tumor burden via ctDNA, are needed. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Short Diagnosis-to-Treatment Interval is Associated with Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma" by Alig et al. My name is Matthew Maurer, and I am a statistician at the Mayo Clinic in Rochester, MN. My oncologic specialty is lymphoid malignancies. I have no relevant conflicts to disclose. The impact of any clinical research critically depends upon participating subjects being representative of the study population afflicted with the disease of interest and research efficiency is markedly enhanced when cohorts can be compared across studies. In newly diagnosed diffuse large B-cell lymphoma (DLBCL), there is a standard group of clinical variables that is typically captured and reported across studies. The International Prognostic Index, or IPI has been utilized as a prognostic model in aggressive lymphoma for nearly 30 years and remains relevant today. The IPI and its components, which consist of age, performance status, LDH, stage, and number of extranodal sites, provide the clinical characteristic backbone for trial eligibility and defining high risk disease in frontline DLBCL trials. Assessment of genomic features of the tumor using pathological techniques such as IHC and FISH can further identify high risk subsets of patients. However, despite these well-tested clinical tools to measure the aggressiveness of the disease, there remains significant heterogeneity in patient presentation and outcomes. Clinically, some patients will present with a real or perceived clinical urgency to initiate therapy as soon as possible. This clinical urgency often precludes these patients from enrolling on frontline trials. My colleagues from the University of Iowa / Mayo Clinic Lymphoma SPORE and I explored this phenomenon in our observational lymphoma cohort study by evaluating the time between a patient's diagnostic biopsy and their initiation of chemotherapy. We found that this simple measure of diagnosis to treatment interval, or DTI, was highly informative in the setting of newly diagnosed DLBCL. Patients with a shorter DTI were more likely to be symptomatic, have advanced stage disease, poor performance status, and elevated LDH. Further, patients with a short DTI had significantly inferior outcomes, even after accounting for the standard clinical details of the IPI. These results were validated in a cohort of clinical trial patients from the French Lymphoma Study Association as well as subsequent studies. These data suggest that clinicians are managing patients with aggressive disease more urgently, and our current set of clinical variables is not sufficient to describe and compare patients across studies. Despite its simplicity and retrospective prognostic ability, DTI lacks specificity as a clinical characteristic for future studies. It can be easily influenced in an individual patient by numerous aspects unrelated to disease biology, such as physician preference or a patient's available access to health care resources. In additional, the typical DTI can vary widely across health systems or institutions. In the paper accompanying this podcast, Alig and colleagues examine the relationship between DTI, conventional risk factors, circulating tumor DNA, and clinical outcomes. A strong association was observed between shorter DTI and increasing tumor burden as measured by baseline metabolic tumor volume and circulating tumor DNA. This is a key biologic confirmation that treatment urgency is directly related to disease biology. Importantly, the authors also showed that ctDNA was a highly informative variable in regards to prognosis in their dataset. ctDNA was an independent prognostic variable after adjusting for the IPI in Cox models for event-free and overall survival, and the prognostic ability of ctDNA was far superior to DTI in univariate models. The association between DTI and disease biology has direct implications for clinical trials in frontline DLBCL. Clinical trials that did not adequately enroll patients in need of urgent therapy were likely biased towards enrollment of patients with lower tumor burden. In particular, single arm trials of novel therapies are particularly at risk, as these results are often evaluated in light of conventional clinical characteristics and compared to previous studies and/or clinical experience. This may also have contributed to the better than expected outcomes on the control arms in recent randomized trials of newly diagnosed DLBCL. Evaluation of tumor burden using ctDNA or metabolic tumor volume should allow us to better understand the impact of a study's design on patient enrollment. The amount of tumor is a long-standing prognostic feature for newly

This podcast considers the impact of exclusion criteria on clinical trials, generalizability, and the complexity of modernizing eligibility while maintaining trial integrity. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Diffuse Large B-cell Lymphoma (DLBCL) Patients. Who Gets Left Behind?" by Khurana et al. My name is Richard Little, and I am at the National Cancer Institute. My oncologic specialty is lymphoid and myeloid malignancies. I am a federal employee with no conflicts of interest to disclose. The authors have contributed a timely and provocative analysis examining the lack of generalizability and disappointing results of repeatedly negative randomized phase 3 trials conducted over the past 15 years failing to improve on R-CHOP. The authors have proposed that these failures may be in part explained by enrollment onto clinical trials patients who are not really representative of those with the disease, because eligibility criteria too often unnecessarily eliminate patients with laboratory values that reflect organ impairment not pertinent to the agents under study. To test this inference, the authors leveraged a unique resource: The Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence, or SPORE. This SPORE is an NCI-funded research project initiated in 2002 and collects data in a uniform manner among consenting participants with newly diagnosed DLBCL who undergo treatment managed by their physician. This rich database enabled the evaluation of data in patients treated with R-CHOP or R-CHOP-like immunochemotherapy. The investigators were able to categorize the SPORE participants in reference to the eligibility criteria of the important phase 3 studies recently conducted as either meeting eligibility of the phase 3 studies or not meeting eligibility due to out-of-range laboratory values. Additionally, the SPORE data in some ways mimics clinical trial data in that events such as disease progression and death are captured, and these outcomes could be evaluated comparatively between patients categorized as clinical trial eligible and not eligible. They indexed 7 trials, and for example, found that 12.9% of the SPORE participants did not meet eligibility for the PHOENIX study—that is the phase 3 trial of ibrutinib-R-CHOP vs placebo-R-CHOP showing no benefit of the addition of ibrutinib. Not surprisingly, those scored as ineligible had worse outcomes compared to those scored as eligible. For example, indexing eligibility for the PHOENIX trial, the overall survival hazard ratio for those scored not eligible versus eligible was 1.49 with a p-value of .002. The median survival of the SPORE cohort scored as ineligible for PHOENIX had a median overall survival of around 80 months, and the median survival for those sored as eligible had not yet been reached. Interestingly, treatment-related deaths were not found to be increased in the SPORE patients scored as ineligible compared to those scored as eligible, but death due to progressive lymphoma was higher among those scored as ineligible. So how does this relate to the inability to improve upon standard DLBCL therapy? Khurana and colleagues' data highlight several features of clinical trials conduct related to trial outcomes. The unnecessary exclusion of patients based on criteria not specific to the treatment can translate into eligible patients having a more favorable prognosis compared to individuals with the disease who are excluded from studies, but who nevertheless are treated with standard therapy used as a control in DLBCL clinical trials. Populating randomized trials with the best prognosis patients can lead to reduced power to detect an outcome difference, even if one exists. But what about the unnecessary exclusion of patients from clinical trials based on laboratory values that reflect organ dysfunction and poor outcomes as shown in the SPORE patients? The authors document unequivocally that those patients deemed ineligible are at higher risk of death due to treatment failure: that is they die due to progressive lymphoma more than the SPORE patients scored as meeting clinical trial eligibility criteria. What we don't know from the study as presented, is whether there were more dose delays and dose reductions among those scored as ineligible. This is fundamental toward an improved understanding of how to repair our clinical trials enterprise in DLBCL. And what I mean by repair, is to broaden and expand clinical trials access to as many patients as possible and to have rigorous design and conduct of trials to detect true signals. There are two essential elements to address, and this data points the way but does not fully answer the questions. To make trials generalizable, we must include as broadly as possible those patients with DLBCL. However, if the SPORE outcomes are explai

This multi-institutional study highlights the heterogeneity of Phyllodes tumors of the breast and the importance of accurate pathology assessment and individualized surgical approaches. LEE WILKE: This JCO podcast provides observations and commentary on the JCO article, Contemporary Multi-institutional Cohort of 550 Cases of Phyllodes Tumors from 2007 to 2017 Demonstrates a Need For More Individualized Margin Guidelines by Rosenberger, et al. My name Lee Wilke and I am a professor of surgery and the Hendrix chair in breast surgery research at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. My oncologist specialty is breast surgical oncology. I have no relationships to disclose related to these studies. As medical students we are asked to adopt an expanded vocabulary to describe a multitude of diseases. The word phyllodes is frequently one of those memorable medical school terms whose origin is Greek and describes a leaf-like growth. Phyllodes are rare tumors accounting for less than 1% of breast malignancies, with just over 2,000 patients diagnosed annually in the United States. Originally, the phyllodes tumor was described as cyst like and, therefore, the historic term cystosarcoma phyllodes was applied. Though these tumors are of connective tissue and fibroepithelial origin, they are infrequently cystic and not a true sarcoma. And therefore, the World Health Organization now classifies them as simply phyllodes tumors. They are importantly, for treatment approaches, sub-categorized into benign, borderline, and malignant based on detailed pathologic review of celularity, atypia, overgrowth, mitotic rate, and the borders of the tumor. Phyllodes tumors are listed in the National Institute of Health's genetic and rare diseases program. On the center's website, surgery is described as the primary treatment for these rare malignancies and 1 centimeter margins or greater are recommended for all subtypes of phyllodes tumors, with a note that these tumors are quote, "often treated with mastectomy", unquote. As specialists caring for patients with breast malignancies, we are rapidly learning that the one-size-fits-all approach is not appropriate, and the same is true for those individuals with phyllodes tumors. In the article that accompanies this podcast, to support a shift towards more individualized treatment, Dr. Laura Rosenberger from Duke University in North Carolina assembled a group of key collaborators from 11 US academic cancer centers to pool and evaluate their treatment approaches and outcomes for patients with phyllodes tumors. The investigators identified a total cohort of 550 patients with phyllodes tumors treated between 2007 and 2017. Consistent with systematic reviews of phyllodes tumor data sets, such as that by Lu et al in Annals of Surgical Oncology, with this JCO publication being the largest, the patients have a median age of 44. The malignant cohort is approximately 10%. And median tumor size is three centimeters, with a range to as high as 29 centimeters. Key facts found within this analysis are that 2% of patients underwent nodal evaluation, all with negative nodes. The addition of either a sentinel node or axillary surgery is not without risks to the patient. And unless the pre-surgical diagnosis raises the question of a simultaneous adenocarcinoma, patients undergoing surgery for a phyllodes tumor should not undergo nodal mapping or axillary surgery as these tumors are primarily local malignancies and do not metastasize via the lymphatic network. This is the first key takeaway from this paper, supporting the work of others that nodal surgery in phyllodes tumors is unnecessary. The second notable finding is the heterogeneity, even among academic medical centers, regarding the surgical approach. Approximately 38% of patients, or 209, proceeded to a second surgical intervention. 51 of these patients, or nearly 10% of the entire cohort, had negative margins at their first surgery. Of the group that underwent a second surgery, only six patients, or 3% of those proceeding to a second intervention, had residual disease. On the opposite end of the spectrum, of those patients with a positive surgical margin, which was 42% of the entire group, 74, or 32% of those with positive margins, did not proceed with a second surgery. These outcomes highlight that even among patients being treated at centers that one would assume would function similarly, patients could have everything from positive margins to additional surgery in the setting of negative margins. What is vital to note at this point, however, is that the recurrence rate for this cohort was only 3.3% or 18 patients-- 15 with a local recurrence and three with a distant recurrence. The recurrences were differentially associated with the phyllodes subtypes, with 1.3% in benign, 5.6% in borderline, and 6.9% in malignant phyllodes. In univariate logistic regression analysis, however, margin status and margin

In this study of cancer operations conducted during the COVID-19 pandemic, rates of pulmonary complications and SARS-COV-2 nosocomial infections were compared between patients operated on in COVID-19-free facilities and those operated on in non-segregated facilities. Because lower rates of pulmonary complications and nosocomial SARS-COV-2 infection were observed in COVID-free facilities, the authors propose a restructuring of surgical facilities and pathways for cancer patients during the COVID-19 pandemic. This JCO podcast provides observations and commentary on the JCO article "Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International Multicenter Comparative Cohort Study, " by Bhangu et al. My name is Ken Tanabe, and I serve as Chief of Surgical Oncology at Massachusetts General Hospital, Professor of Surgery at Harvard Medical School, and Deputy Clinical Director of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts. My oncologic specialty is surgical oncology. The devastation and destruction brought about by the SARS-CoV-2 pandemic is difficult to fully comprehend. At time of this podcast there are more than 28 million infections worldwide and nearly 200,000 deaths in the United States alone. Hospitals and healthcare networks have been uniformly challenged to provide care and safety for patients and providers. In response to this initial wave, elective operations were cancelled as a strategy to increase critical care resources, preserve Personal Protective Equipment – or PPE, and re-deploy surgical team members to support care for COVID-19 patients. On a worldwide basis, this amounted to cancelation of a substantial number of operations. And a significant fraction of these backlogged operations was for cancer. Once hospitals recognized they could handle the size and peak of the initial wave, they resumed elective cancer operations. Some hospitals had the capacity to create COVID-19 free surgical units for these operations, as a strategy to reduce the risk of cross-infection of patients. Subsets of cancer patients are known to be at higher risk from COVID-19 morbidity and mortality, including those with lung cancer. However, creation of parallel pathways for COVID and non-COVID cancer patients diverts resources and is associated with significant costs. The relative value of this maneuver is not known, but is of critical importance, particularly in light of catastrophic hospital finances created by the pandemic. In the article that accompanies this podcast, the authors studied the impact of creation of COVID-19-free surgical facilities. Specifically, they gathered data from 445 hospitals in which patients underwent operation either in a COVID-19-free surgical pathway, or alternatively underwent operation in a hospital that did not have separate, COVID-free surgical units. The study included over 9,000 patients that underwent cancer operations during the pandemic. Hospitals in 54 countries are included, though the United Kingdom, Italy, Spain and United States accounted collectively for over 60% of the patients. A surgical facility was defined COVID-19 free if it had a policy of segregation of COVID-19 patients in three specific areas of the hospital: the operating rooms, the ICUs, and the inpatient units. Conversely, a surgical facility was not considered COVID-19 free if this segregation was absent in any of these three areas. There are several key findings. First and foremost, patients who underwent surgery within COVID-free units were younger and had fewer comorbidities compared to patients operated on in non-segregated surgical units. After adjustment for these differences, pulmonary complication rates were lower amongst patients operated on in COVID-free units compared to those operated on in non-segregated surgical units. The post-operative SARS-COV-2 infection rate was lower in COVID-free surgical units – 2.1% compared to the 3.6% observed in non-segregated units. The preoperative COVID testing rate was higher in the COVID-19-free surgical units. Specifically, the testing rate was 39% in the COVID-19-free surgical units and only 23% in the non-segregated facilities. However, in a sensitivity analysis for patients with a negative preoperative swab test, the benefit of COVID-19 free pathways remained apparent. The authors conclude it is likely that differences in SARS-CoV2 transmission rates are responsible for the lower pulmonary complication rates in those operated on in COVID-19-free surgical units. The authors cite these observations as the basis for their recommendation for, quote, "major international redesign of surgical services -- based on local available resources -- to provide elective cancer surgery in COVID-19-free surgical pathways." End quote. Of note, there are many hospitals and healthcare networks in the U.S., let alone worldwide, that don't have the resources required to create COVID-19-free operating rooms, I

This podcast reviews the results of the whole genome sequencing study by Samur and colleagues that identified a genomic signature associated with superior survival in patients with newly diagnosed multiple myeloma. Disclosures: SAH has served on advisory boards or as a consultant for Adaptive Biotechnologies, Amgen, Celgene, Genentech, GSK, Oncopeptides, Sorrento; Takeda; has received research funding from Oncopeptides. This JCO Podcast provides observations and commentary on the JCO article "Genome-Wide Somatic Alterations in Multiple Myeloma Reveals a Superior Outcome Group" by Samur et al. My name is Sarah Holstein, and I am an Associate Professor at the University of Nebraska Medical Center in Omaha, Nebraska in the United States. My oncologic specialty is plasma cell dyscrasias. I do not have any relationships to disclose related to these studies. The clinical heterogeneity of myeloma has long been appreciated as it is clear there is a broad range of disease behavior, with some patients having indolent disease and others having very aggressive disease. As a result, there has been significant interest in developing risk stratification systems that classify patients into different risk groups, thus providing some information about prognosis and potentially inform treatment decisions. Historically, staging systems were based on factors related to tumor burden. However, it is increasingly evident that the underlying disease biology is a key modulator of risk. Our ability to detect disturbances in the myeloma genome has changed dramatically over time. Metaphase karyotyping represents our lowest "power of magnification". These studies led to the recognition that in general, hyperdiploidy involving odd-numbered chromosomes is associated with lower-risk disease while high-risk disease can involve translocations of chromosome 14, monosomy 13 and monosomy 17. Use of fluorescent in-situ hybridization (FISH) allowed for a higher power of magnification and identification of more subtle chromosomal abnormalities. Next, gene expression profiling studies utilizing small panels of genes, enabled classification of patients into different risk categories, although there was little concordance between the panels used in the various studies. The advent of deep whole genome sequencing technology has facilitated a much more "high-powered" view of the myeloma genome. In the article that accompanies this podcast, diagnostic bone marrow specimens were obtained from 183 patients enrolled in the IFM/DFCI 2009 study. This phase 3 study enrolled newly diagnosed transplant-eligible patients (up to age 65). All patients received three cycles of lenalidomide, bortezomib, dexamethasone (RVD) induction, underwent stem cell collection and then received consolidation with either 5 cycles of RVD or a single autologous stem cell transplant followed by 2 cycles of RVD. Of note, in the French portion of this study, all patients subsequently received one year of lenalidomide maintenance, while in the US portion, all patients received lenalidomide until progression. The French portion has already been published and showed a 14 month PFS benefit for the transplant arm compared to the non-transplant arm. Results from the US portion have not yet been released, but I would speculate that the PFS and OS for both arms will be superior to the French counterparts, given the existing data supporting the benefit of prolonged lenalidomide maintenance. Deep whole genome sequencing, with a median tumor depth of 75X, was used to interrogate the myeloma genome. Mutational signatures were based on identified single nucleotide variants, small insertions and deletions. The genomic scar score (GSS) was calculated based on allele-specific copy number alterations. A GSS of 5 or less was the cut-off for inclusion in the low GSS group. The goals of the study were to describe mutational loads and processes in order to establish genomically-defined subgroups, gain insight into patterns of evolution from clonal to subclonal mutations, and correlate these findings with clinical outcomes and more traditional risk factors. There were several key findings. First, mutational load varied amongst myeloma subgroups, with hyperdiploid myeloma having the lowest mutational load and t(14;16) having the highest mutational load. Second, analysis of mutational patterns led to identification of five separate mutational processes that contributed to eight mutational signatures. These five processes included: 1) an age-related process, 2) an AID/APOBEC process, 3) somatic hypermutation, 4) DNA repair, and 5) processes with unidentified etiology including the clock-like signature. Samur et al., found that these various processes contributed to different myeloma subgroups in different ways. For example, the age-related process was high in hyperdiploid myeloma, the APOBEC-related process was high in t(14;16) myeloma, the clock-like signature was high in t(4;14) myeloma and the DNA repair pr

This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients. Transcript This JCO Podcast provides observations and commentary on the JCO article "Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children's Oncology Group" by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose. Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important. Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane. As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don't know how longer follow-up will influence these results. Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children's Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children's Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%. In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients th

This podcast reviews the results of the observational study by Ladas and colleagues that found protective associations between dietary antioxidant intake and the occurrence of bacterial infections and mucositis. TRANSCRIPT This JCO podcast provides observations and commentary from the JCO article "The Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia, A Report From the DALLT Cohort" by Ladas et al. My name is Wendy Demark-Wahnefried, and I am Webb Endowed Chair and Professor of Nutrition Sciences at the University of Alabama at Birmingham, as well as the Associate Director for Cancer Prevention and Control at the O'Neal Comprehensive Cancer Center at UAB in Birmingham, Alabama in the United States. I do not have any relationships to disclose regarding these studies, and my review is grounded by the fact that I am a nutrition scientist with particular expertise in cancer survivorship. The topic of nutrition and cancer generates a great deal of interest, especially once individuals are diagnosed with cancer. This is particularly germane with regard to antioxidants, since some scientists hypothesize that high levels of antioxidants may be beneficial for cancer control while others speculate that high levels may prevent apoptosis of cancer cells and actually impede the effectiveness of cancer therapy. However data are sparse, and there are very few studies of high quality, therefore the paper by Ladas and colleagues is both timely and important. The study enrolled 794 children ages 1 through 18 who were diagnosed with acute lymphoblastic leukemia. These children were enrolled from 10 institutions across the continental United States, Puerto Rico, and Canada. The children or their guardians completed age appropriate food frequency questionnaires that assessed dietary intake over the previous month and did so at two time points, soon after diagnosis and after the induction phase of treatment, or roughly a month after the first questionnaire. The nutrients that were studied were vitamins A, C, and E, as well as alpha, beta and total carotenoids-- these are the substances in plant foods that give the food its color-- and zinc. It should be noted that the antioxidant selenium was not studied. Nutrient intake was statistically analyzed in relation to bacterial infection and higher grade mucositis or inflammation of the digestive tract resulting in mouth sores or ulceration of the esophagus. Nutrient intake also was studied in relation to disease-free survival and minimal residual disease. Children were followed for up to 10 years. Of the 513 participants who completed the dietary surveys at both time points, 23% experienced a bacterial infection, and 16% experienced higher grade mucositis. Only 9% had higher levels of minimal residual disease, and 2% did not achieve complete remission. Results showed that children having diets with higher levels of antioxidants had a significantly lower risk of bacterial infection, with risk lowered by 10% to 27%, depending upon the antioxidant. Similarly, children having diets with higher levels of antioxidants had a significantly lower risk of higher grade mucositis, with risk lowered by 17% to 67%, again, depending upon the antioxidant. Importantly, evidence of protection was only observed for nutrients obtained through the diet and not nutritional supplements. In addition, no significant associations were observed between antioxidant intake, either through diet or supplements, and disease-free survival. This study has several strengths, in that it involved the participation of a diverse and ample sample of several children and their parents across several sites. Furthermore, data were collected at two time points. As always, there are limitations, and when relying on self-reported data there is always the risk of inaccurate reporting and misclassification. In addition, and thankfully, the number of children who had higher levels of minimal residual disease or who had not experienced complete remission was very small. And therefore, the study was likely under power to detect any associations between nutrient intake and these outcomes. Finally, because these results emanate from an observational study, cause and effect cannot be inferred. Thus the title of this manuscript, which begins with "The Protective Effects" in quotations, may be a bit of an overstatement. So what are the implications of this study? As noted previously, there are few data in this area, therefore more studies are needed to either confirm or refute these results. And such research is necessary in other cancer populations, such as among adults with other cancers who receive different therapies. Until such time, these data reinforce that a healthy diet may associate with lower risk of common treatment-related toxicities. It is noteworthy that investigators were only able to detect protective associations from antioxidants from dietary sources and not from s

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer" by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer. In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria. Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients. In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified. The authors found that among almost 4,000 women tested, those meeting current NCCN guideline crite

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer" by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology. Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment. Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months. As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response. One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months. So you may be wondering, what's the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT. There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related. The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from sep

This podcast will discuss the findings from a phase II trial of gemcitabine, cisplatin and PARP inhibitor therapy in germline BRCA/PALB2 mutant pancreatic cancer and discuss an optimal treatment strategy in this setting. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "A Randomized, Multi-Center, Phase II Trial of Gemcitabine, Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation" by O'Reilly et al. My name is Daniel Renouf, and I am a medical oncologist at the BC Cancer Vancouver Centre in Vancouver, Canada. My oncologic specialty is pancreatic cancer. In this podcast, we will be discussing an important and evolving area that is changing our standard treatment strategies for pancreatic cancer. Progress has been slow for pancreatic adenocarcinoma, which is now the third leading cause of cancer-related death in North America and is projected to become the second leading cause of cancer-related death within the next decade. Modest gains in our treatments have been achieved with new chemotherapy combinations, including FOLFIRINOX and gemcitabine and nano-albumen bound-paclitaxel, yet still the majority of patients diagnosed with advanced disease will live for less than one year. There is a critical need for improved treatment options as well as clinically relevant predictive markers to guide our therapeutic decision making. The first clinically important predictive marker in pancreatic cancer is germline BRCA/PALB2 mutation status, which is present in 5-9% of pancreatic adenocarcinomas. Multiple translational studies and case series have demonstrated distinct molecular features of these tumors, as well as unique clinical characteristics. Germline BRCA/PALB2 mutant pancreatic adenocarcinomas have been noted to be sensitive to platinum agents and be associated with a better prognosis. Despite this data, and a general acceptance within the community that platinum agents are the preferred therapies in this setting, there is minimal prospective trial data specifically assessing the activity of platinum combinations in germline BRCA/PALB2 mutant pancreatic adenocarcinoma. At a plenary session at ASCO 2019 and its subsequent publication, the POLO trial assessed the role of maintenance therapy with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib), compared to placebo, in patients with metastatic pancreatic adenocarcinoma and germline mutations in BRCA/PALB2 who had responded or had stable disease after initial therapy with FOLFIRINOX. This was a positive trial, demonstrating that maintenance olaparib significantly improved progression-free survival compared to placebo. There was no difference noted in overall survival, but this data was not yet mature. The role of combining a PARP inhibitor with platinum-based chemotherapy as upfront treatment in this patient population is yet to be defined. A previous Phase I trial of gemcitabine, cisplatin and the PARP inhibitor veliparib determined a recommended phase II dose for velipirib in this combination and demonstrated promising efficacy in germline BRCA-mutant pancreatic adenocarcinoma. In the article that accompanies this podcast, Dr. O'Reilly and colleagues report on the results of a phase II prospective trial comparing gemcitabine and cisplatin versus gemcitabine, cisplatin and veliparib in patients with advanced pancreatic adenocarcinoma with germline aberrations in BRCA/PALB2. In the trial, patients with locally advanced or metastatic pancreatic cancer who had not received chemotherapy in the advanced setting, had a good performance status, and who harbored germline aberrations in BRCA/PALB2 were randomized. A total of 50 patients were enrolled, and the results demonstrated good efficacy in both arms, with a response rate of 74.1% in the veliparib arm and 65.2% in the control arm. Median progression-free survival was 10.1 months and 9.7 in the veliparib and non-veliparib arms respectively, and median overall survival was 15.5 and 16.4 months. Of note, for the entire cohort, 2-year overall survival was notably high at 30.6%, and 3-year overall survival was 17.8%. Grade 3-4 toxicities, including neutropenia, thrombocytopenia, and anemia were greater in the veliparib arm. The authors concluded that gemcitabine and cisplatin demonstrated significant activity in BRCA/PALB2 germline mutant pancreatic adenocarcinoma, and the addition of concurrent veliparib did not improve efficacy. Given this promising data, it was concluded that gemcitabine and cisplatin should be considered a standard treatment for BRCA/PALB2 germline mutant pancreatic adenocarcinoma. This is an important trial, as it is one of the first to specifically assess platinum chemotherapy prospectively in this patient population and has important implications for treatment strategies for pancreatic cancer, the first of which is that testing for germline BRCA/PALB2 mutations should now be considered standard of c

Towards improved characterization of immune-related adverse events in the setting of pre-existing autoimmune disease. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Immune Checkpoint Inhibitor Therapy in Patients with Preexisting Inflammatory Bowel Disease", by Abu-Sbeih et al. My name is Katy Tsai, and I am Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of California, San Francisco. My oncologic specialty is the treatment of advanced melanoma and non-melanoma skin cancers. Immune checkpoint inhibitors, referred to as ICIs in this podcast, have transformed the landscape of treatment options in oncology. While ICIs were first approved for the treatment of advanced melanoma in 2011, since that time, ICIs have shown activity in a variety of other histologies. Anti-PD-1 or anti-PD-L1, with or without anti-CTLA-4, are now approved for the treatment of lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and many others. While ICIs can result in durable responses, their continued use can be limited by the development of immune-related adverse eventsimmune-related adverse events. Because these events are believed to be autoimmune in nature, there are intuitive safety concerns about ICI use in patients with known autoimmune disease. Can patients with pre-existing autoimmune disease be safely treated with ICI? Are these patients more likely to experience immune-related adverse events related to their autoimmune disease? Is this risk increased if their autoimmune disease is severe, with a history of required immunosuppression? These are all important questions faced by healthcare providers, questions which are not well studied due to the exclusion of patients with known autoimmune disease from pivotal ICI clinical trials. To address these questions, Abu-Sbeih and colleagues chose to focus on ICI use in patients with pre-existing inflammatory bowel disease. This is a clinically relevant population of interest, given the relatively high incidence of immune-related diarrhea and colitis with ICI use; these immune-related adverse events occur in almost half of patients receiving combination anti-CTLA-4 and anti-PD-1 or PD-L1, about one-third of patients receiving anti-CTLA-4, and less frequently in patients receiving anti-PD-1 or PD-L1 alone. Abu-Sbeih and colleagues conducted a retrospective, multicenter study in which 102 patients – half with Crohn's disease, half with ulcerative colitis – received ICI between 2010 and 2019. 17 patients received anti-CTLA-4, and 85 received anti-PD-1 or anti-PD-L1. This is a notable cohort of patients, as previous meta-analyses have reported on the safety of ICI use in much smaller numbers of patients with inflammatory bowel disease, and with less detailed clinical characterization of their inflammatory bowel disease. Univariate and multivariate logistic regression were used to assess the risk of gastrointestinal, or GI, adverse events, and was compared to a control population of 11,377 ICI-treated patients without inflammatory bowel disease, from the same participating institutions. An important observation made by the authors was that the rate of GI immune-related adverse events in the inflammatory bowel disease cohort was significantly higher at 41%, compared to 11% in the non-inflammatory bowel disease cohort. Univariate analysis identified anti-CTLA-4 (given as monotherapy or in combination) as a risk factor for GI immune-related adverse events compared to anti-PD-1/L1 therapy but showed only a tendency toward significance in multivariate analysis, as did inflammatory bowel disease involving the colon. Although none of the collected clinical variables reached significance in multivariate analysis, the authors' analysis of outcomes in the inflammatory bowel disease cohort is illuminating. Of the 41 inflammatory bowel disease patients who developed diarrhea, 51% had peak grade 3 or 4 diarrhea, 76% received glucocorticoids, and 29% required additional immunosuppression with infliximab or vedolizumab. 4% developed colonic perforation, with half of those patients requiring surgical intervention. Also of note, patients who were identified as having active inflammatory bowel disease within 3 months of ICI start had higher grade diarrhea compared to patients with inactive inflammatory bowel disease. Endoscopy data were also available for 48 inflammatory bowel disease patients. Interestingly, of the 41 patients who were noted to have normal or mild inflammatory findings, 18 (43%) developed any GI immune-related adverse events, 5 (12%) of which were grades 3-4. In the 7 patients with moderate/severe inflammatory findings, 5 (71%) had GI immune-related adverse events of any grade, 2 (29%) of which were grades 3-4. Despite the higher rate of GI immune-related adverse events and associated complications in the inflammatory bowel disease cohort compared to the non-inflammatory bowel disease cohor

This podcast describes a study examining aerobic capacity in a cohort of over 1200 adult survivors of childhood cancer and related impairments of cardiac, pulmonary and neuromuscular body systems, to understand how aerobic capacity influences all-cause mortality. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer' by Ness et al. My name is Kristin Campbell, and I am a licenced physical therapist and associate professor in the Faculty of Medicine at the University of British Columbia in Vancouver, Canada. My oncologic specialty is in rehabilitation, primarily related to breast cancer. Exercise intolerance is a global measure of functional capacity that reflects the complex integration of body systems. It is well established in the general population that exercise intolerance is predictive of future cardiovascular health and mortality. Whether this relationship also existed for adult survivors of childhood cancer was examined by Ness and colleagues in the article that accompanies this podcast. . In the largest study to date of its kind, this manuscript reports on a comprehensive and methodologically rigorous examination of exercise intolerance measured by a gold standard maximal cardiopulmonary exercise test in over 1200 adult survivors of childhood cancer who are part of the St. Jude's Lifetime Cohort Study. The first main finding is the low levels of exercise capacity in this sample of childhood cancer survivors despite a relatively young mean age of 35 years. The observed maximal aerobic capacity, or VO2peak, ranged on average between 25-27 ml/kg/min, which fall into the "poor" or "very poor" categories of age and sex matched normative values. Compared to 285 community controls who were friends or family members of the cohort patients, the observed maximal aerobic capacity values for childhood cancer survivors were on average 22% lower. In fact, these values are actually more consistent with values seen in healthy adults in their seventies or eighties. Furthermore, the low value of maximal aerobic capacity may also be an underestimate. Thirteen percent of individuals in the St. Jude's cohort who agreed to participate in the study were not cleared to undertake the maximal cardiopulmonary exercise test due to recent diagnosis of cardiac or pulmonary disease, or lab values and symptoms indicating cardiac or pulmonary issues. This suggests that the prevalence of exercise intolerance may be even greater in a real-world clinical setting than that observed in this cohort. To examine the association between exercise intolerance and mortality, the authors defined exercise intolerance as a maximal aerobic capacity of A unique feature of this study is that the authors also undertook comprehensive measures of host, treatment, and lifestyle factors to better understand how these factors influence exercise intolerance. These additional measures included cardiac imaging at rest, autonomic response, measured by blood pressure response to the maximal graded exercise test, standard pulmonary function testing, quadriceps strength testing, and peripheral sensorimotor function using the modified total neuropathy scale. This data provides a rare look into the acute and chronic responses to exercise of the cardiovascular, pulmonary, autonomic and neuromuscular systems in those exposed or not exposed to cardiotoxic agents and will appeal to those an interest in exercise physiology. Odds of exercise intolerance were highest with reporting Of note, the type of treatment received impacted the presentation of exercise intolerance. Lower exercise tolerance was observed in individuals who received >350 mg/m2 of anthracyclines, >30 Gy of chest radiation, >20 Gy of cranial radiation and receipt of carboplatin. As a result, the authors suggest that even asymptomatic childhood cancer survivors who have received these treatments be screened by medical providers for any required medical management prior to recommending or implementing an exercise program. Furthermore, while ejection fraction of 1.5 SD above age- and sex-predicted increased the odds of exercise intolerance with an odds ratio of 1.71 in those exposed to cardiotoxic agents and an odds ratio of 1.29 in those not exposed to cardiotoxic agents. The authors suggest that the use of echocardiology derived strain be expanded from current published guidelines from the American Society of Clinical Oncology on Prevention and Monitoring of Cardiac Dysfunction to identify early cardiac dysfunction in childhood cancer survivors with exercise intolerance and normal ejection fraction. The study does have some key limitations. It is cross-sectional in design, making it difficult to assign temporal relationships between impairments in body systems and exercise tolerance. For example, is it the treatment that causes impairments in body systems that then limit exer

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study" by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care. About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only. The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months. The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI. 41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available. The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts. By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%. Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during t

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology. Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens. This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability. At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase. Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy. Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed. The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection. Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonst

This podcast evaluates results from a phase II clinical trial of pembrolizumab for relapsed Mycosis Fungoides and Sezary Syndrome in the context of the current systemic treatment landscape for this disease. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study" by Khodadoust et al. My name is Jennifer Amengual, and I am an Assistant Professor of Medicine at the Columbia University Irving Medical Center in New York, New York, USA. My oncologic specialty is lymphoma. Mycosis fungoides, otherwise known as MF, and Sezary Syndrome, its leukemic variant, are rare subtypes of cutaneous T-cell lymphoma. Although most patients with MF have indolent disease, those with advanced stage MF often experience resistance to systemic therapy with a persistent and progressive disease course, which has a negative impact on overall well-being and survival. Patients may have intense pruritus, which can then put them at increased risk for staphylococcus infection, sepsis and in turn can trigger disease flare. Advanced-stage MF is a chronic disease that is not considered curable; therefore, it is necessary to consider management strategies that provide symptom relief and can be maintained over a long period of time. Most patients cycle through a multitude of therapies, often including skin-directed and, later, systemic therapies. Many of the acceptable therapies are derived from retrospective studies or single-arm trials; therefore, it is not possible to objectively compare outcomes and toxicity. In order to put the outcomes of pembrolizumab in context of other acceptable treatment modalities, I will discuss some of these treatments now. Systemic retinoids, such as bexarotene, are taken orally and can induce an overall response of 45-55%. The drug is well tolerated but can lead to hypertriglyceridemia and hypothyroidism, requiring monthly monitoring and frequent treatment with lipid-lowering agents and thyroid hormone replacement. Low-dose methotrexate, administered either orally or by intravenous infusion weekly, can lead to response rates between 30 and 50%. Common side-effects include mucositis, cytopenias and gastrointestinal upset. Pralatrexate is a novel antifolate drug that when studied using half the dose of that which is approved for PTCL , induced a 45% response rate for patients with MF. The treatment is also well tolerated, with the most common side-effects being mucositis and thrombocytopenia. There are 2 histone deacetylase inhibitors approved for use in MF and Sezary Syndrome. Both romidepsin and vorinostat have overlapping toxicity profiles, including gastrointestinal disturbances, fatigue, anorexia, and cytopenias. Romidepsin is also associated with ECG abnormalities. In patients with cutaneous T cell lymphoma, romidepsin has demonstrated a response rate of 34% and is associated with a median duration of response of 15 months. Vorinostat, an oral drug, has demonstrated a response rate of 30%. Recently, 2 biologics have been in used for patients with MF. Brentuximab vedotin is an antibody drug conjugate which targets the surface marker CD30 and brings monomethyl auristatin E into the cell. It is associated with a response rate of 70% in MF. Responses are significantly better in those with greater than 5% of CD30 expression. The most common side-effect is peripheral neuropathy. Mogamulizumab is a humanized antibody directed against the chemokine receptor CCR4. This agent was studied in a randomized trial compared to vorinostat, where it led to a PFS of 7.7 months and response rate of 28%. The most common adverse events were attributed to infusion reactions, rash, diarrhea, and fatigue. There was also an increased risk of graft-versus-host disease in patients who subsequently went on to allogenic transplant, which needs to be considered when using this treatment strategy. As you can see, there are many different approaches to the treatment of advanced-stage MF and Sezary Syndrome, and the drugs I have discussed do not encompass an exhaustive list. Immune checkpoint antibodies against Programmed cell death protein 1 otherwise known as PD-1 interfere with inhibitory signaling pathways expressed on exhausted T-cells and wake up these cells allowing them to perform anti-tumor activities. The investigators rationalize the use of PD-1 inhibitors in MF and Sezary syndrome given PD-1 dysfunction and altered expression on MF cells and the skin microenvironment. The Cancer Immunotherapy Trials Network performed a multicenter phase II single-arm study of pembrolizumab in 24 patients across 8 centers with relapsed or refractory MF or Sezary Syndrome. Of the 24 patients enrolled, 9 had MF and 15 had Sezary syndrome. Most had advanced disease represented by tumor stage disease, erythrodermic presentation, or were stage IIIB or higher. Patients received a median of 4 prior lines of systemic the

This podcast discusses the results and implications of a recent study on gender bias in speaker introductions at an international oncology conference. This JCO Podcast provides observations and commentary on the JCO article "Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference" by Duma et al. My name is Dr. Tatiana Prowell. I am an Associate Professor of Oncology at Johns Hopkins Kimmel Cancer Center and Breast Cancer Scientific Liaison at the U.S. Food and Drug Administration in Silver Spring, Maryland. My oncologic specialty is breast cancer. In the article that accompanies this podcast, Duma and colleagues report the results of a retrospective observational study of speaker introductions at two consecutive years of ASCO Annual Meetings. The investigators hypothesized that female speakers in oral sessions would be introduced with a professional form of address less frequently than male speakers. For the purposes of the study, they defined a professional address as use of a title such as Professor or Doctor, followed by the speaker's full name or last name, or the speaker's full name followed by doctoral degree. A team of four male and four female reviewers analyzed 781 video recordings of oral sessions from the 2017 and 2018 ASCO Annual Meetings and recorded the gender of the introducer and speaker and how the speaker was introduced. They found that female speakers received a professional form of address 62% of the time whereas male speakers were introduced professionally 81% of the time, a difference that was statistically significant. Duma and her colleagues also assessed whether the gender of the introducer was associated with a difference in the likelihood of receiving a professional introduction. They found that male moderators introduced female speakers professionally a little more than half the time, whereas they introduced men professionally in 80% of cases. Interestingly, when serving as introducers, women were more likely than men to include a professional form of address, which they did about three-quarters of the time, regardless of whether they were introducing men or women. Perhaps the most striking result of the study was that one in six female speakers was introduced by her first name only, a surprising degree of informality for a high-profile conference like the ASCO Annual Meeting, which draws more than 40,000 attendees per year. By comparison, male speakers were introduced by first name alone in just 3% of presentations. In a multivariate analysis that included gender, degree, academic rank and geographic location of the speaker's institution, male speakers were 2.5 times more likely to receive a professional introduction compared to female speakers. This study adds to a growing body of literature in medicine investigating the prevalence of gender bias in speaker introductions. For example, previous studies of speaker introductions over a 3 year period of Mayo Clinic Internal Medicine Grand Rounds and at an American Society of Colon and Rectal Surgeons Annual Meeting reported similar findings. In both cases, female speakers were less likely than men to be introduced using a professional form of address, and women introducers more consistently referred to speakers by a professional title, regardless of whether the speaker they were introducing happened to be a man or a woman. This study raises two key questions: why do we see this, and how can we fix it? A speaker introduction, especially at an international conference, is by definition a formal ritual, and yet one so familiar to us that we may have lost sight of its purpose. It would be easy enough for speakers to introduce themselves. Every speaker has an opening slide that shows his or her name and institutional affiliation. So why choose someone, and often someone well-known within the field, whose role is to introduce the speakers at all? What leads us to say, "Dr. Carol Greider is Bloomberg Distinguished Professor, Director of Molecular Biology and Genetics at Johns Hopkins University, and a recipient of the 2009 Nobel Prize in Medicine"? I believe we do this for two reasons. First, formal introductions provide a moment, however brief, to demonstrate our collective respect for the speaker and his or her scientific contributions. Second, the information in the introduction signals to any who are not familiar with the speaker that the person is credible, knowledgeable, and worthy of our attention. Although more than 50% of medical school matriculants and about 40% of medical school faculty are women, they remain underrepresented at higher academic ranks and in leadership roles. Only about one-quarter of full professors are women, and fewer than 1 in 5 department chairs are women. Women are also less likely than men to be the first or senior author of manuscripts and thus less likely to be standing at the podium. As a result, the names and work of women in medicine may well be less familiar to the

Treatment-free survival is a novel endpoint in immunotherapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma" by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology. Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word "cure" is not completely out of mind. Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990's for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma. Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment. In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death. With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity. These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health. If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of immune suppressants. To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time follow

TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Progression of Disease Within 24 Months (POD24) in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune-Infiltration" by Dr. Tobin and colleagues. My name is Dr. Carla Casulo, and I am Associate Professor of Medicine, Hematology and Oncology at the Wilmot Cancer Institute of the University of Rochester in Rochester, NY, USA. My oncologic specialty is Lymphoma. Follicular lymphoma is the most frequently occurring indolent non-Hodgkin lymphoma and has a long natural history, with median overall survival nearing two decades. Patients with follicular lymphoma may experience a variable clinical course, with periods of long remission punctuated by episodes of recurrent lymphoma requiring re-treatment. Among all patients, up to one third will have early disease recurrence, defined as occurring within 24 months of diagnosis. Please note that progression of disease within 24 months will be referred to as POD24 for the remainder of this podcast. These patients have inferior survival, ranging from 25-50% at 5 years. Consequently, POD24 has become a robust and well accepted indicator of identifying high-risk patients. The implications of POD24 were first identified through our analysis of the National Lymphocare Study, which sought to test the hypothesis that time to disease progression had an impact on subsequent patient outcomes. 588 patients treated with RCHOP were included. Patients with POD24 were defined as early progressors, and those without relapse or death within 24 months were defined as the reference group. Patients with POD24 had OS of 50% at 5 years compared to 90% in the reference group. These findings have subsequently been independently validated by numerous investigators worldwide, corroborating the adverse prognostic impact of an early disease related event in follicular lymphoma. The largest of these validation studies pooled individual patient data from 5,453 patients on 13 Clinical Trials using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation. In the FLASH analysis, we identified that male gender, poor performance status, high follicular lymphoma international Prognostic index (FLIPI) score, and elevated baseline beta 2 microglobulin B2M as predictors of early death and progression. Moreover, it confirmed POD24 as an early clinical endpoint of poor survival in follicular lymphoma that should be utilized to identify patients for prospective clinical trials. The current status of biomarkers in follicular lymphoma has emerged from a wealth of clinical and laboratory-based factors to classify risk, towards a biologic based, molecular approach merging clinical factors with our current understanding of the follicular lymphoma genomic landscape. There are numerous well-established and emerging clinical prognostic indices used at the time of diagnosis in follicular lymphoma that can help discriminate general outcome. These include the FLIPI and FLIPI -2. To an extent, these prognostic markers can identify subsets of patients with an expected POD24 with a sensitivity between 60-78%, and a specificity between 56-58%. However, in an attempt to use a precision approach, investigators from the German Low-Grade Lymphoma Study Group harmonized clinical and pathologic data to create a clinico-genetic risk model aimed at more accurate risk prognostication in patients receiving front line chemoimmunotherapy. They performed deep DNA sequencing from formalin fixed pre-treatment biopsies to analyze the mutational status of genes in 151 patients with follicular lymphoma tumor samples. The resulting prognostic tool, called the m7-FLIPI, distilled down 74 genes into 7 genes with non-silent mutations occurring at a variant allele frequency of 10% or greater, and combined these with high risk FLIPI status and ECOG performance status. These included genes that increased risk of progression, including EP300, FOX01, CREBBP, CARD11, and those that decreased risk of progression, including EZH2, ARID1A, and MEF2B. The cumulative risk score was calculated by combining relative weights of these genes in a multivariate analysis predicting failure-free survival. This m7-FLIPI score was tested to identify POD24 but only captured about 50% of patients as high risk. A later model included only 3 genes, including EP300, FOX01 and EZH2, performance status and FLIPI score. Defined as the POD24-PI, this was more sensitive at identifying POD24 patients but did not outperform other metrics due to lower specificity. Biologic classification of POD24 patients remains an ongoing international research priority to seek actionable targets that might change the natural history of follicular lymphoma and improve survival of patients more likely to have morbidity and death from their disease. Several years ago, in the pre-rituximab era, the Leukemia and Lymphoma Molecular profiling project identified the importance of the f

This podcast summarizes the findings of the Lunenburg Lymphoma Biomarker Consortium systematic evaluation of MYC rearrangements in DLBCL, and discusses the prognostic impact of MYC, BCL2 and BCL6 rearrangements, and implications for FISH testing in newly diagnosed DLBCL. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma - A Study by the Lunenburg Lymphoma Biomarker Consortium" by Rosenwald et al. My name is Jeremy Abramson, and I am an attending physician at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. My oncologic specialty is lymphoma. MYC rearrangements occur in approximately 10% of diffuse large B-cell lymphomas and have been associated with a worse prognosis. When the MYC translocation occurs in concert with translocations of BCL2, BCL6, or both, initial series have suggested particularly poor outcomes with few patients achieving long term survival with conventional therapies. This entity has been classified in the current WHO classification as high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 and is more conventionally known as double (or triple) hit lymphoma. Though initial series painted a grim prognosis for these patients, more recent larger series have suggested that approximately 40% of double hit lymphoma patients may be cured, and that outcomes may be improved with more intensive regimens such as dose-adjusted EPOCH-R. Most of these published series to date, however, continue to be limited by significant selection bias whereby cases with the most aggressive clinical or histopathologic features are likelier to be tested for MYC translocations, thus potentially excluding more prognostically favorable patients. The small size of series to date has also made it difficult to assess more granular questions in MYC translocated diffuse large B cell lymphoma, hereafter referred to as DLBCL, such as the prognostic impact of MYC translocations when occurring without other translocations, the impact of translocation partner with MYC (Ig or non-Ig gene locus) in double hit lymphoma, and the significance of MYC/BCL6 double hit lymphomas which are far less common than MYC and BCL2. Another practical question is who should we be testing for MYC translocations in the first place? Do we need to test every new case of DLBCL? Or should we routinely test only an enriched population, such as those with MYC protein expression by immunohistochemistry, or GCB-like DLBCLs, which include the majority of double hit lymphomas? In the article that accompanies this podcast, the Lunenberg Lymphoma Biomarker Consortium presents the single largest and most systematic analysis to date of MYC translocations in DLBCL, and sheds significant light on many of the most outstanding questions in this population. The Consortium studied over 2000 cases of DLBCL with available tissue and clinical data, drawn from large prospective cooperative group studies as well as population-based registries in Canada, the United Kingdom and the United States. The median age of the cohort was 66 years, and the median follow up was mature at greater than 6 years. All patients were treated with R-CHOP or R-CHOP-like therapy. MYC rearrangements were found in 11% of patients. One third of these occurred as a sole rearrangement, 39% in concert with a BCL2 rearrangement, 15% with a BCL6 rearrangement, and 12% with both (i.e. triple hit lymphoma). Patients with MYC rearrangements had higher risk features by the IPI score than the entire DLBCL population, and patients with double/triple hit lymphoma had higher clinical risk factors than patients with MYC rearrangements alone. Patients with double or triple hit lymphoma had a significantly inferior outcome in terms of both progression free and overall survival compared to the overall DLBCL cohort, while no negative prognostic impact was conferred by a MYC translocation alone. Notably, the prognostic impact was only observed in the first 2 years from diagnosis. They also compared the 31 MYC/BCL6 double hit patients with 82 MYC/BCL2 double hits, and found similar outcomes in the groups, validating that MYC/BCL6 double hit lymphomas should be considered high risk along with their BCL2 translocated counterparts. Prognosis for triple hit lymphoma was no worse than double hit lymphoma. Perhaps most striking, however, was how well double and triple hit lymphoma patients did when compared to previously published retrospective studies. In this comprehensive evaluation by the Consortium, approximately 60% of double and triple hit lymphoma patients remained progression free beyond 5 years, and two thirds remained alive. These remarkable data suggest that the majority of double and triple hit lymphomas identified by broad screening of the DLBCL population may be cured with chemoimmunotherapy and should offer

This podcast discusses the work of Sheetz and colleagues describing the impact of centralization of high-risk cancer surgery within health care systems and networks in the United States. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Centralization of High-Risk Cancer Surgery Within Existing Hospital Systems" by Sheetz et al. My name is Stephen Edge, and I am Vice President of Healthcare Outcomes and Policy and Professor of Surgery and Oncology at the Roswell Park Comprehensive Cancer Center and the University at Buffalo in Buffalo, NY. My oncologic specialty is surgical oncology. Recent years have seen substantial consolidation of hospitals and practices into networked care systems. The benefits of health networks may include efficiencies of scale, better ability to thrive in the shifting health care economy, and enhanced quality. In the article that accompanies this podcast, Dr. Sheetz and colleagues at the University of Michigan studied the impact of health care networks on the outcome of high-risk cancer surgeries for pancreas, esophagus, lung, colon and rectal cancer. They examined the distribution of these surgeries in health care networks, and the relationship between outcomes and the degree of centralization of surgeries to a high-volume network hospital. There is a well-established relationship between hospital case volume and operative mortality for complex cancer surgery, most pronounced for pancreas and esophagus cancer. Some countries now mandate regionalization of these procedures to high volume centers. Most, but not all, studies show that regionalization improves outcomes for these procedures. Organized regionalization of cancer surgery in the United States has been limited though market forces have led to some consolidation of high-risk surgeries. This has been encouraged through recommendations of the Leapfrog Group that for the last 25 years has set minimum hospital volume standards for high risk surgeries. Sheetz and colleagues used the Medicare Provider Analysis and Review (MedPAR) files that include all beneficiaries of Medicare Part A to identify persons age 65 and older undergoing pancreatectomy, esophagectomy, lung resection, colectomy and proctectomy for the years 2005 – 2014. They used American Hospital Association data to identify hospital characteristics such as size, teaching status and which hospitals are in the same health system if any. They combined these data with information from the National Inpatient Sample to derive estimates of the total number of cases of each type beyond Medicare beneficiaries. They defined a "high volume hospital" and "high volume system" as one that met the Leapfrog Group volume criteria; and centralization of surgery as the proportion of surgeries of each type performed at the highest volume hospital in a given health network. Outcomes assessed were 30-day mortality after surgery, major complications, and hospital readmission. The procedures most centralized in networks were pancreatectomy and esophagectomy with a mean of 71% and 51%, respectively. However, for pancreas surgery 74% and for esophagus surgery 84% of systems did not meet or have a hospital that met the Leapfrog Group volume recommendations for pancreatectomy. Complications were about 20% lower for pancreas and esophagus surgery at health systems with the highest surgery centralization. The impact on complications of lung and colorectal surgery was less. More important was the reduction in risk-adjusted 30-day mortality. For pancreas and esophagus surgery the mortality at the most centralized systems mortality was 60% and 53% lower, respectively, then the least centralized systems. The absolute rates dropped from 8.9% to 3.7% for pancreas and 10.3% to 4.8% for esophagus surgery. The reduction for lung resection was less and there was no significant mortality difference for colorectal surgery. Importantly, the team observed the same level of reduction associated with system surgery centralization for low volume and high-volume systems, and those with and without a high-volume hospital. Certainly, this study is not without its limitations. Because the MedPAR files include primarily fee-for-service Medicare, they had to estimate the total number of cases. They did not have specific information on the health systems or the distance of patients from a high-volume center. They did not know the systems' governance relationships or the degree of coordination between system hospitals, services and providers. However, the study reinforces the well-established volume-outcome relationships in the context of hospitals with common governance. While individual surgeons may be excellent at low volume hospitals the finding of a greater relative impact on mortality than complications suggest that it not just the surgeon, but that high-volume hospitals with their larger teams and resources are less likely to "fail to rescue" a patient with a major complication. Thi

Dr. Osama Rahma, an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute, discusses the role of MSI in gastric cancer. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability as a Biomarker in Gastric Cancer" by Pietrantonio et al. My name is Osama Rahma, and I am an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute in Boston, Massachusetts. My oncologic specialty is Gastrointestinal Cancer and Cancer Immunotherapy. Despite the advances in surgical approach and perioperative multimodalities in gastric cancer, the recurrence rate remains over 50%. While many patients benefit from perioperative chemotherapy many others don't derive such benefits and experience toxic side effects. Accordingly, there is an unmet need to identify prognostic markers to guide chemotherapy decisions in the neoadjuvant and adjuvant settings. Microsatellite instability has been well established as a prognostic marker in colon cancer that correlates with better overall survival and potential lack of benefit from adjuvant chemotherapy in stage II disease. The question is whether microsatellite instable gastric tumors have similar behavior? To answer this question, subgroups analyses of patients with MSI high tumors were performed in both the MAGIC and the CLASSIC trials which established perioperative ECF chemotherapy in non-Asian population and adjuvant capecitabine and oxaliplatin in Asia, respectively as the standard of care in resectable gastric cancer. Although MSI tumors were found to be less likely to benefit from chemotherapy, the low incidence of MSI tumors in both trials of 8-10% made it very challenging to draw meaningful conclusions. In the article that accompanies this podcast, Pietrantonio et al performed individual patient level data meta-analysis testing the prognostic significance of microsatellite instability in both the MAGIC and CLASSIC trials. In addition, the analysis included the ARTIST study, which tested adding radiation to adjuvant capecitabine and cisplatin in Asia and the ITACA-S study which tested adjuvant FOLFIRI, docetaxel and cisplatin vs 5-fluorouracil and folinic acid in Europe in radically resected gastric cancer. The meta-analysis included 1556 patients, 63% Asian and 37% Europeans. Patients were stratified using microsatellite instability status and based on whether they received multimodality therapy in all 4 trials or surgery only in the MAGIC and CLASSIC trials. 7.8% of patients had MSI high tumors and 70.8 % received multimodality treatment. Consistent with prior reports of individual trials, patients with MSI high tumors had better outcomes compared to MSI low or MSS tumors. Specifically, the 5-year disease free survival rate was 71.8% vs 52.3% and 5-year overall survival was 77.5% vs 59.3%. MSI remained a significant independent prognostic factor for improved disease-free survival and overall survival in a multivariate analysis in addition to Asian ethnicity, low TNM staging, and receiving multimodality therapy. In addition, MSI was noted to be more prevalent in the Asian population and was a better prognostic factor in Asians compared to Europeans. Importantly, MSI high tumors did not benefit from perioperative chemotherapy with 5-year disease free and overall survival of 70% and 75%, respectively for those who received chemotherapy compared to 77% and 83% for MSI high patients who did not receive chemotherapy. In contrast patients with MSI low or MSS experienced benefit from perioperative chemotherapy compared to surgery alone. Finally, MSI status did not affect post-recurrence survival. However, this was limited by the small number of MSI high patients who experience disease recurrence. This study has several limitations including its retrospective nature, the relatively small number of patients with MSI high tumors of 121, and the heterogenicity of administered treatment in the 4 trials including different regimens of neoadjuvant and adjuvant chemotherapy with or without radiation. In addition, D1 surgery was performed in Europe while D2 surgery was performed in Asia. In summary, I think this study supports the adoption of microsatellite testing as a routine biomarker in patients with operable gastric cancer. The result of microsatellite testing should be discussed in a multidisciplinary fashion since perioperative chemotherapy may result in more harm than benefit in MSI high tumors. This study among others highlights the unique behavior of microsatellite instable tumors which is driven by their unique immune profile including increased T-cell infiltration and activation due to higher mutational load and neoantigens compared to microsatellite stable tumors. PD-1 inhibitors are effective in more than 50% of MSI tumors in the advanced setting and in 15-25% of gastric tumors with positive PD-L1 expression. Accord

This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA. My oncologic specialty is Pediatric Radiation Oncology. This important manuscript summarizes the results of Children's Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma. The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15. Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy. Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable. This left 97 patients evaluable for response and concurrent chemoradiotherapy. Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution. All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes. A boost to the nasopharynx and residual gross nodal disease was prescribed based on response. The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower. Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy. The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported. This trial was limited to patients age 18 years and younger and consisted primarily of American patients. It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis. Most patients are teens since nasopharynx cancer is vanishingly rare in younger children. The majority were male, and nearly half were African-American. Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population. In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer. The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology. Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma. It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given. Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation. It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer. While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose. In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction. Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse. The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper. Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults. The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies. The rate of second malignancy is also much higher in young patients. The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled. It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined. In that case, they can be targeted with radiotherapy to decrease the risk of relapse. This approach has been shown to be effective in achieving cure in adults. It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity. Indeed, it is unclear whether the 3rd cycle

This JCO Podcast provides observations and commentary on the JCO article "Maintaining Outstanding Outcomes Using Response and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531" by Twist et al. My name is Javed Khan, and I am Deputy Chief and Senior Investigator at the Genetics Branch and an Attending for the Pediatric Oncology Branch of the National Cancer Institutes of the NIH in Bethesda, Maryland. My oncologic specialty is Pediatric Hematology Oncology. Childhood cancer is a life-threatening disease where survival rates have increased exponentially to over 75% over the past three decades. However, this has come at a considerable cost with significant incidence of late effects including hearing loss, scoliosis, hypothyroidism, growth and development delay, infertility, psychological, emotional, cognitive and neurological sequelae, and secondary malignancies. Most of these late effects have been attributed therapy including chemotherapy, surgery and radiation. In the manuscript that accompanies this podcast, Twist et al report on the results of the Children's Oncology Group study ANBL0531, whose primary aim was to reduce therapy for subsets of children aged =95% for the entire cohort. Neuroblastoma is an extracranial pediatric malignancy of neural crest origin that has often been described as an enigmatic cancer due to its significant clinical, molecular and biological heterogeneity. For example, some patients with widely metastatic disease are cured with minimal or no therapy whereas others have relentless progression to death despite intensive therapies. There has been considerable progress in dissecting out the causes of this heterogeneity and developing prognostic biomarkers to stratify the risk based on several clinical, histological and molecular markers. At the time this clinical study was performed, and the manuscript written, the authors stratified patients using several clinical and biologic parameters including age, the International Neuroblastoma Staging System, MYCN amplification status, the International Neuroblastoma Pathology Classification of histopathology, and tumor DNA index. An additional marker utilized in this study was loss of heterozygosity determination of the tumors at chromosome bands 1p36 and 11q23. This stratification strategy has led to the identification of low and high-risk groups where therapy is more clearly defined and patients with low risk have excellent outcome for most patients with surgery alone and watchful waiting. For high-risk disease, significant strides have been made using a combination of surgery, aggressive chemotherapy, radiation followed by Chimeric Antibody 14.18 anti GD2 therapy, GM-CSF, IL-2 and Isotretinoin, however the five-year survival remains guarded at 40-50%. In the intermediate-risk group, the subject of this study, although the 5-year survival rates of 90-95% have been achieved, this group is significantly heterozygous raising the possibility of reducing therapy for subsets of patients within this group. This was the motivation for this study. Thus, the goal of this clinical protocol, ANBL0531, was to refine the minimal therapy needed to achieve excellent outcomes for patients with intermediate-risk neuroblastoma, with the aim to maintain an overall 3-year OS rate of > 95% for the entire cohort. Patients were stratified into Groups 2, 3, or 4, who were assigned to receive a minimum of 2, 4, or 8 cycles of chemotherapy, respectively. Chemotherapy was identical to that used on a previous study A3961. Reduction of therapy was planned to be achieved for patients with biologically favorable tumors (Groups 2 and 3) by using the achievement of Partial Response (PR) to chemotherapy +/- surgery to be the endpoint of therapy, rather than the achievement of Very Good Partial Response (VGPR) as was previously used on A3961. If the treatment endpoint was not achieved after completion of the scheduled chemotherapy courses, additional cycles of therapy could be administered, and patients re-evaluated following every 2 cycles to determine if the treatment endpoint has been achieved. VGPR, a more stringent response criteria, was used for Group 4 patients which includes those with age1). These patients also received Isotretinoin (13-cis-retinoic acid, Accutane) for maintenance therapy, as they would have previously received this treatment on high-risk protocols. Thus, these patients would receive a significant reduction in therapy compared to prior studies. These patients were closely monitored by interim stopping rules. Rescue therapy for this study for patients with an inadequate response to initial therapy and for patients with progressive, non-metastatic disease utilized standard cyclophosphamide and topotecan. Reduction of therapy was also planned and achieved on their study by reducing potential surgical morbidity for patients with stage 4S disease, who would no longer be required to unde

This JCO Podcast provides observations and commentary on the JCO article "Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)" by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation. CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2. Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage. Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells. While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4. Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5. Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6. Therefore, a head-to-head comparison was the natural next step. The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP. The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013. Seventy-four % had stage III/IV disease and 12% high IPI disease. Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R patients. Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6. There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted. In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small. There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen. Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL? In other words is this a case of "déjà vu all over again"?. This trial recruited slowly, 524 patients over more than 8 years, with 2 (20% of the phase II study5) were excluded. Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease. Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative. While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to

This JCO Podcast provides observations and commentary on the JCO article "Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study" by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology. With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for "cure" of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer. CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm. In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm. The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes. A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar

This JCO Podcast provides observations and commentary on the JCO article 'Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy' by Yang et My name is Ann LaCasce, and I am an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, USA. My oncologic specialty is lymphoma. This podcast discusses the recent paper evaluating the risk of late relapse in patients with diffuse large B-cell lymphoma who are event free 24 months after diagnosis. The goal of upfront chemoimmunotherapy in patients with diffuse large B-cell lymphoma (DLBCL) is the permanent eradication of disease. In the era of rituximab, few studies with sufficient follow-up have examined the risk of late recurrence. An analysis of patients with DLBCL from the University of Iowa/Mayo and validated in a separate cohort from the French Study Group of Adult Lymphoma demonstrated that patients who were alive and disease free at 24 months from diagnosis had overall survival rates equivalent to the age and sex matched general population. Despite this finding suggesting cure, late relapses are not uncommon. In this manuscript, patients enrolled in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence with newly diagnosed diffuse large B-cell lymphoma or DLBCL with concurrent indolent lymphoma were identified. 847 of the 1324 patients treated with chemoimmunotherapy with or without radiotherapy between 2002 and 2015 were event free at 24 months. These patients were subsequently analyzed for late relapse. The majority of patients (87%) had DLBCL without evidence of co-existing indolent lymphoma. With a median follow-up of 62.9 months, 78 patients developed recurrent disease, and the cumulative incidence of late relapse was approximately 7% at 3 years, 9% at 5 years and 10 % at 8 years after achieving EFS24. Of the patients who developed recurrent lymphoma, 55 had DLBCL alone at baseline and 23 had DLBCL with concurrent indolent lymphoma. Among the patients with DLBCL alone. 36 developed recurrent DLBCL and 13 ad indolent lymphoma (12 with follicular lymphoma and 1 with marginal zone lymphoma). 6 patients did not have pathologic confirmation of disease subtype at the time of recurrence. For the 59% of patients with cell of origin data determined using the Hans algorithm, rates of relapse in patients with DLBCL alone did not differ between those with germinal center derived (GCB) versus non-GCB subtypes. Individuals with GCB DLBCL were more likely to relapse with indolent lymphoma. Of the 23 patients with concurrent indolent lymphoma at baseline, 9 relapsed with DLBCL and the remaining 11 relapsed with indolent lymphoma 10 of whom had the same subtype at initial presentation (7 with follicular lymphoma, 1 marginal zone lymphoma, 1 chronic lymphocytic leukemia, one unspecified). One patient who had current DLBCL and FL relapsed with MCL and the subtype was unknown in 3. Patients with concurrent indolent lymphoma at initial diagnosis were more likely to experience late relapse which was driven by indolent recurrence. In multivariable analysis, concurrent indolent lymphoma and GCB subtype were independent predictors of relapse. In patients with DLBCL alone, GCB subtype was associated with indolent relapse but not DLBCL relapse. Advanced stage and higher IPI score were associated with higher risk of recurrent DLBCL but not indolent relapse. In terms of outcome, median survival after recurrence was approximately 39 months after EFS24, 30 months for those with DLBCL and the median was not reached in patients with indolent lymphoma. This study emphasizes the importance of long- term follow-up of our patients with DLBCL. Hematologists/oncologists typically see patients frequently after the completion of initial therapy but over time, visits become less frequent or not at all for some patients who remain in remission beyond the 5 year mark. Multiple studies have examined surveillance strategies in this setting. The likelihood of identifying recurrent disease in an asymptomatic patient with a normal physical exam is extremely low. In addition, there is no clear evidence that surveillance imaging or early detection of an asymptomatic recurrence impacts on overall survival. This is particularly true for patients who relapse with indolent disease, some of whom may be followed expectantly. Others may be candidates for low-dose palliative radiation or reduced intensity therapies. The National Comprehensive Cancer Network Guidelines , which are widely used by physicians as well as payors to determine insurance coverage, recommends symptom guided imaging in patients with a history of early stage DLBCL and CT scans no more often than 6 months for up to 2 years after the completion of therapy in patients with advanced stage disease. Imaging is associated with false positives, radiation exposure and is expensive for our health care system. In additi

This JCO Podcast provides observations and commentary on the JCO article "Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis" by Abu-Sbeih et al. My name is David Oh, and I am an Assistant Professor at the University of California, San Francisco. My oncologic specialty is genitourinary medical oncology and cancer immunotherapy. While immune checkpoint inhibitors, or ICIs, can lead to durable responses even when other standard therapies have failed, their therapeutic window is often limited by immune-related adverse events or IRAEs which are thought to be autoimmune in nature. Immune-mediated diarrhea and colitis are a frequent IRAE with ICIs, affecting up to a third of patients receiving anti-CTLA-4, approaching half of patients receiving anti-CTLA-4 in combination with anti-PD-1 or anti-PD-L1, and less frequently patients receiving anti-PD-1 or anti-PD-L1 alone. Since there is often overlap between IRAEs and response or survival with ICIs, and IRAEs such as colitis can require interruption of treatment and immunosuppression in patients who may have failed other treatment options, many providers are faced with an important question: is it safe to resume ICIs after patients have initial diarrhea and colitis, and what are the risk factors for another episode of diarrhea and colitis? To address this question, which has not been well studied, Abu-Sbeih and colleagues in this issue of JCO performed a retrospective multicenter analysis of patients who had initial immune-mediated diarrhea and colitis requiring ICI interruption, and then subsequently resumed ICI from 2010 to 2018. From a starting population of 550 patients with initial diarrhea and colitis with ICI, they identified 167 patients who subsequently resumed ICI for a re-treatment rate of 30%. This represents a notable cohort with this degree of clinical annotation. For their initial therapy leading to diarrhea and colitis, about half of these patients had initially received anti-PD-1 or PD-L1 therapy, and a quarter each had initially received either anti-CTLA-4 therapy or combination. The majority of these patients had melanoma, with a smaller proportion of non-small cell lung and genitourinary cancer patients. At the time of re-treatment, 80% of these patients received an anti-PD-1 or anti-PD-L1 alone, while the others were re-treated with anti-CTLA-4 alone. An important observation by the authors was that upon re-treatment of the 167 patients, 57 patients, or about a third, experienced recurrent diarrhea and colitis requiring permanent discontinuation of therapy. The grade of diarrhea and colitis most frequently seen was less severe, graded as less than or equal to Grade 2. As expected, 81% of these patients with recurrent diarrhea and colitis received steroids, while 12% of patients required further immunosuppression with either infliximab or vedolizumab which blocks the integrin alpha-4-beta-7. Univariate and multivariate analyses were used to identify risk factors for recurrent diarrhea and colitis upon ICI resumption. Univariate analysis identified more severe initial diarrhea and colitis as a risk factor for having recurrent diarrhea and colitis on ICI re-challenge. Initial severity was determined either by longer duration of initial symptoms or requirement for initial immunosuppression. Multivariate analysis confirmed initial severity as a risk factor, and also found that a lower risk of recurrent diarrhea and colitis was associated with initial anti-CTLA-4 use, as well as with choice of anti-PD-1 or anti-PD-L1 therapy at the time of re-challenge regardless of their initial therapy. Importantly, even though resumption of anti-CTLA-4 was associated with a higher risk of recurrent diarrhea and colitis, the severity of recurrence, as determined by frequency of immunosuppression and grading of diarrhea and colitis, were actually similar to when anti-PD-1 or anti-PD-L1 were resumed. Overall, then, despite the limitations of retrospective analysis, this work provides evidence from a substantial patient cohort across tumor and treatment types that recurrent diarrhea and colitis with ICI retreatment following initial interruption for diarrhea and colitis may occur in less than half of patients and is generally less severe. Furthermore, the risk of recurrent diarrhea and colitis is less likely in patients who had less severe episodes of initial diarrhea and colitis, who previously received initial anti-CTLA-4, or who are re-challenged with anti-PD-1 or anti-PD-L1 therapy. Although the choice of anti-PD-1 or anti-PD-L1 for re-treatment reduces the risk of recurrent diarrhea and colitis, the actual severity of recurrent episodes is similar to re-treatment with anti-CTLA-4 therapy. As a practical matter this can provide guidance to providers about whether to consider ICI resumption, and which agents to consider, based in part of characteristics of their initial treatment and IRAE. This will be particularly important for patients

This JCO Podcast provides observations and commentary on the JCO article "PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study" by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma. Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens. As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure. One important question has been: how best to distinguish those disparate groups? Over the years, various prognostic scoring systems have been devised. The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors. However, only 7% of patients are in both the most and least favorable groups. The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection. Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens. More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets. FDG-PET scanning has revolutionized our management of patients with lymphoma. In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score. In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected. In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma. This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle. Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy. Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy. Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy. Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death. Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores. Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown. Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors. But we are clearly doing this all wrong. Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy? Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma. High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies. Unfortunately, those tests do not provide a target against which to direct a specific agent. In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome. Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goa

This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma. Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget's Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients. Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor. Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years. This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in. SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma. It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases. It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma. This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC. In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks. At the time of progression on placebo, patients were allowed to crossover to Regorafenib. Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients. Here is what they found. At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017. Given the crossover design, there was no overall survival seen with a p-value of 0.62. In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions. Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response. Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work. There are a number of meaningful observations that come from this trial. First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral. While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use. I would hope the guidelines change to reflect these publications soon. Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children's Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months. They concluded that, "This evaluation provides a baseline for disease progression in a population of children and yo